Conjugated estrogens

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Identification

Summary

Conjugated estrogens is a mixture of estrogens used in estrogen replacement therapy for menopause and hypoestrogenism, used in the treatment of various malignancies, and used in the treatment of postmenopausal osteoporosis.

Brand Names

Congest, Duavee, Duavive, Premarin, Premphase 28 Day, Prempro 0.625/2.5 28 Day

Generic Name

Conjugated estrogens

DrugBank Accession Number

DB00286

Background

The conjugated estrogens are noncrystalline mixtures of purified female sex hormones obtained either by its isolation from the urine of pregnant mares or by synthetic generation from vegetal material. Both of these products are later conjugated to natrium sulfate by ester bonds in order to make them more water soluble.^10,7

The conjugated estrogen product contains a mix of estrogen from which about 50% is represented by estrone sulfate followed by 25% of equilin sulfate, 15% of 17-alpha-dehydroequilenin sulfate, 3% of equilenin sulfate, 5% of 17-alpha and 17-beta-dihydroequilenin sulfate, 2% of 17-alpha-estradiolsulfate and 3% of 17-beta-estradiolsulfate. It also presents a large number of unidentified molecules with weak estrogenic activity as well as non-human molecules when it is obtained from pregnant mares urine.⁷

The conjugated estrogen mixture was approved for marketing in US in 1942 based on the efficacy against certain conditions. However, until 1986 official clinical trials were performed and this product was determined to be effective for the treatment of osteoporosis.⁹ The currently approved product of conjugated estrogens was developed by Wyeth Ayerst and FDA approved in 2003.¹¹

Type

Small Molecule

Groups

Approved

Synonyms

Conjugated equine estrogens
Conjugated estrogens
Estrogens, Conjugated
Estrogens,conjugated

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Pharmacology

Indication

The conjugated estrogens are indicated for several different conditions including:

Treatment of moderate to severe vasomotor symptoms due to menopause.
Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
Palliative treatment of breast cancer in appropriately selected patients with metastatic disease.
Palliative treatment of androgen-dependent carcinoma of the prostate.
Preventive therapy of postmenopausal osteoporosis.²

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Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Dose Form
Treatment of	Abnormal uterine bleeding	••••••••••••		•••••••••
Treatment of	Atrophic vaginitis	••••••••••••		•••••• ••••••• •••••••• •••••••
Treatment of	Kraurosis vulvae	••••••••••••		•••••
Symptomatic treatment of	Menopause	••••••••••••	••••••••••• ••••••••••••••	••••••• •••••••• •••••••
Symptomatic treatment of	Metastatic breast cancer	••••••••••••		••••••

Associated Therapies

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Pharmacodynamics

The binding of estrogens to the estrogen receptor produces the activation of nuclear receptors in order to bind to estrogen response elements in certain target genes. This mechanistic cascade results in histone acetylation, alteration of chromatin conformation and the initiation of transcription of certain specific drugs.¹⁰

In preclinical studies, the conjugated estrogens are known to have a similar estrogenic potency than estrone and the equilin components of the conjugated estrogens have similar potency in the liver when compared to bioidentical estradiol.⁴ It has also been tested and confirmed that conjugated estrogens present a selective estrogen receptor modulator profile which allows it to have a large beneficial effect on the bone and cardiovascular system.⁵

Clinically, the administration of conjugated estrogens is known to promote vasomotor stability, maintain genitourinary function, and normal growth and development of female sex hormones. It has also been shown to prevent accelerated bone loss by inhibiting bone resorption and restoring the balance of bone resorption. In the hormonal area, it is shown to inhibit luteinizing hormone and decrease the serum concentration of testosterone.⁸

Mechanism of action

The conjugated estrogens, equally to the normal physiological estrogen, work by agonistically binding to the estrogen receptors alpha and beta. The estrogen receptors vary in quantity and proportion according to the tissues and hence, the activity of this conjugated estrogens is very variable.²

The activity made by the conjugated estrogens is driven by the increase in the synthesis of DNA, RNA and various proteins in responsive tissues which in order will reduce the release of gonadotropin-releasing hormone, follicle-stimulating hormone and leuteinizing hormone.⁸

The specific mechanism of action cannot be described only in terms of total estrogenic action as the pharmacokinetic profile, the tissue specificity and the tissue metabolism is different for each component of the product.⁷

Target	Actions	Organism
AEstrogen receptor beta	agonist	Humans
AEstrogen receptor	agonist	Humans

Absorption

The conjugated estrogens are well absorbed in the gastrointestinal tract and the maximum plasma concentration of the conjugated estrogens is reached after 7 hours depending on the estrone component.¹ The maximal plasma concentration of conjugated estrogens after multiple doses of 0.45 mg is reported to be of 2.6 ng/ml with an AUC in the steady state of 35 ng.h/ml.² Unconjugated estrogens are known to be cleared from the circulation at a faster rate than their ester forms.³

Volume of distribution

The physiological distribution of estrogens in the body is very similar to what is seen in endogenous estrogens and hence, it is widely distributed.² The conjugated estrogens are mainly found in the sex hormone target organs.¹²

Protein binding

Conjugated estrogens are bound to plasma proteins and this bound state can represent around 50-80% of the administered dose.⁸ It circulates in the blood mainly bound to sex-hormone binding globulin and albumin.²

Metabolism

The conjugated estrogens are metabolized by a number of different pathways. One of the metabolic pathways of the conjugated estrogens is driven by the action of the cytochrome isoenzyme CYP3A4.¹ On the other hand, the conjugated estrogens can also be processed by a dynamic equilibrium of metabolic interconversion and sulfate conjugation. Some of the principal metabolic reactions of the conjugated estrogens are driven by the conversion of 17beta-estradiol to estrone and the further change to estriol. A portion of the administered conjugated estrogens will remain in the blood as sulfate conjugates which serve as a circulating reservoir for the generation of new estrogens.²

In the endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin as well as 2-hydroxy and 4-hydroxy estradiol. This hydroxylation process is very large in various of the components of the conjugated estrogens and hence, the major metabolites in urine are known to be 17-ketosteroid-16-alpha-hydroxy estrone, 16-alpha-hydroxy-17-beta-dihydro equilin and 16-alpha-hydroxy-17-beta-dihydroequilenin.³

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Conjugated estrogens

Route of elimination

The conjugated estrogens are eliminated mainly in the urine.¹ In this renal elimination, it is possible to find 17 beta-estradiol, estrone, estriol, as well as the glucuronide and sulfate conjugates of the estrogens.²

Half-life

The median half-life of the conjugated estrogens is reported to be of 17 hours.¹

Clearance

The reported normal clearance rate for estrogens is of approximately 615 L/m2.⁶

Adverse Effects

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Toxicity

The reported oral LD50 in the rat is of more than 5000 mg/kg.¹³ Serious overdosage symptoms have not been reported. There have been only reports of nausea, vomiting, and withdrawal in bleeding in females.^Label

Long-term continuous administration of estrogens is correlated to increased risk on the incidence of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.^Label

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Conjugated estrogens may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abametapir	The serum concentration of Conjugated estrogens can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Conjugated estrogens can be increased when combined with Abatacept.
Abciximab	Conjugated estrogens may decrease the anticoagulant activities of Abciximab.
Abemaciclib	Abemaciclib may decrease the excretion rate of Conjugated estrogens which could result in a higher serum level.

Food Interactions

Take with or without food. Consult individual product monograph for specific instructions.

Products

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Product Images

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
C.E.S.	Tablet	0.625 mg	Oral	Bausch Health, Canada Inc.	1963-12-31	Not applicable
C.E.S. Tablets	Tablet	0.3 mg	Oral	Valeant Canada Lp Valeant Canada S.E.C.	1997-03-14	2014-07-30
C.E.S. Tablets	Tablet	0.9 mg	Oral	Valeant Canada Lp Valeant Canada S.E.C.	1997-03-14	2014-07-30
C.E.S. Tablets	Tablet	1.25 mg	Oral	Valeant Canada Lp Valeant Canada S.E.C.	1963-12-31	2014-07-30
Congest	Tablet	2.5 mg	Oral	Laboratoire Riva Inc.	1990-12-31	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Apo-conest Tab 0.3mg	Tablet	0.3 mg	Oral	Apotex Corporation	1994-12-31	2009-10-09
Apo-conest Tab 0.625mg	Tablet	0.625 mg	Oral	Apotex Corporation	1994-12-31	2009-10-09
Apo-conest Tab 0.9mg	Tablet	0.9 mg	Oral	Apotex Corporation	1994-12-31	2009-10-09
Apo-conest Tab 1.25mg	Tablet	1.25 mg	Oral	Apotex Corporation	1994-12-31	2009-10-09
Apo-conest Tab 2.5mg	Tablet	2.5 mg	Oral	Apotex Corporation	1994-12-31	2009-10-09

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Duavee	Conjugated estrogens (0.45 mg/1) + Bazedoxifene acetate (20 mg/1)	Tablet, film coated	Oral	U.S. Pharmaceuticals	2013-11-15	Not applicable
Duavee	Conjugated estrogens (0.45 mg/1) + Bazedoxifene acetate (20 mg/1)	Tablet, film coated	Oral	Wyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.	2013-10-03	Not applicable
Duavee	Conjugated estrogens (0.45 mg/1) + Bazedoxifene acetate (20 mg/1)	Tablet, film coated	Oral	U.S. Pharmaceuticals	2013-11-15	Not applicable
Duavive	Conjugated estrogens (0.45 mg) + Bazedoxifene (20 mg)	Tablet, multilayer, extended release	Oral	Pfizer Europe Ma Eeig	2016-09-08	Not applicable
DUAVIVE	Conjugated estrogens (0.45 MG) + Bazedoxifene (20 MG)	Tablet, delayed release	Oral	Pfizer Europe Ma Eeig	2015-03-31	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Esterified Estrogens and Methyltestosterone	Conjugated estrogens (1.25 mg/1) + Methyltestosterone (2.5 mg/1)	Tablet, film coated	Oral	Seton Pharmaceuticals	2010-05-05	2017-01-26
Esterified Estrogens and Methyltestosterone	Conjugated estrogens (0.625 mg/1) + Methyltestosterone (1.25 mg/1)	Tablet, film coated	Oral	Seton Pharmaceuticals	2005-10-10	2017-02-23

Chemical Identifiers

UNII: IU5QR144QX
CAS number: 12126-59-9

References

Synthesis Reference

US20020156303

General References

Authors unspecified: Conjugated oestrogens/bazedoxifene. Aust Prescr. 2017 Jun;40(3):114-115. doi: 10.18773/austprescr.2017.039. Epub 2017 May 10. [Article]
Cada DJ, Baker DE: Conjugated estrogens and bazedoxifene. Hosp Pharm. 2014 Mar;49(3):273-83. doi: 10.1310/hpj4903-273. [Article]
Bhavnani BR: Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc Soc Exp Biol Med. 1998 Jan;217(1):6-16. [Article]
Kuhl H: Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005 Aug;8 Suppl 1:3-63. doi: 10.1080/13697130500148875. [Article]
Cline JM: Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors. Birth Defects Res B Dev Reprod Toxicol. 2007 Apr;80(2):126-46. doi: 10.1002/bdrb.20112. [Article]
Hembree WC, Bardin CW, Lipsett MB: A study of estrogen metabolic clearance rates and transfer factors. J Clin Invest. 1969 Oct;48(10):1809-19. doi: 10.1172/JCI106147. [Article]
Lauritzen C. and Studd J. (2005). Current management of the menopause. Taylor and Francis. [ISBN:0-203-62272-3]
Arthur H. Jeske (2017). Mosby's Dental Drug Reference - E-Book. Elsevier Health Sciences. [ISBN:9780323511216]
Kelsey J. and Marcus R. (2000). Menopause. Academic Press.
NIH [Link]
FDA approvals [Link]
Pfizer [Link]
Pfizer Safety Data Sheet [File]

External Links

KEGG Drug: D04070
PubChem Substance: 46505680
ChemSpider: 9532
RxNav: 4099
ChEBI: 8389
ChEMBL: CHEMBL2106240
Therapeutic Targets Database: DNC001150
PharmGKB: PA164754789
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Conjugated_estrogens

FDA label

Download (434 KB)

MSDS

Download (393 KB)

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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Not Available	Completed	Not Available	Dementia	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Pelvic Organ Prolapse (POP) / Postoperative pain	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Postmenopausal	2	somestatus	stop reason	just information to hide
Not Available	Completed	Other	Abnormal Mammogram / Mammographic Density	1	somestatus	stop reason	just information to hide
Not Available	Completed	Other	Osteoarthritis of the Hands	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Wyeth pharmaceuticals inc
Duramed research inc
Teva womens health inc
Roche palo alto llc

Packagers

Amerisource Health Services Corp.
Apotheca Inc.
A-S Medication Solutions LLC
Cardinal Health
Caremark LLC
Comprehensive Consultant Services Inc.
Dept Health Central Pharmacy
Direct Dispensing Inc.
Direct Pharmaceuticals Inc.
Dispensing Solutions
Diversified Healthcare Services Inc.
Duramed
Group Health Cooperative
H.E. Butt Grocery Co.
H.J. Harkins Co. Inc.
Heartland Repack Services LLC
Kaiser Foundation Hospital
Lake Erie Medical and Surgical Supply
Liberty Pharmaceuticals
Mallinckrodt Inc.
Martin Surgical Supply
Mckesson Corp.
Medvantx Inc.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Noxzema Inc.
Nucare Pharmaceuticals Inc.
Patheon Inc.
PCA LLC
PD-Rx Pharmaceuticals Inc.
Pharmaceutical Utilization Management Program VA Inc.
Pharmacy Service Center
Pharmedix
Physicians Total Care Inc.
Preferred Pharmaceuticals Inc.
Prepackage Specialists
Primedics Laboratories
Remedy Repack
Resource Optimization and Innovation LLC
Rite Aid Corp.
Sandhills Packaging Inc.
Southwood Pharmaceuticals
Talbert Medical Management Corp.
Tya Pharmaceuticals
Vangard Labs Inc.
Wyeth Pharmaceuticals

Dosage Forms

Form	Route	Strength
Tablet	Oral	0.3 mg
Tablet	Oral	0.625 mg
Tablet	Oral	1.25 mg
Tablet	Oral	2.5 mg
Tablet, film coated	Oral
Tablet	Oral
Tablet, delayed release	Oral
Tablet, multilayer, extended release	Oral
Tablet, film coated	Oral	0.625 mg
Tablet, coated	Oral	0.3 mg
Cream
Cream	Topical; Vaginal	0.625 mg/1g
Injection, powder, lyophilized, for solution	Intramuscular; Intravenous	25 mg/5mL
Tablet	Oral
Tablet, extended release	Oral	0.3 mg
Tablet, extended release	Oral	0.625 mg
Tablet, extended release	Oral	1.25 mg
Tablet, film coated	Oral	0.3 mg/1
Tablet, film coated	Oral	0.45 mg/1
Tablet, film coated	Oral	0.625 mg/1
Tablet, film coated	Oral	0.9 mg/1
Tablet, film coated	Oral	1.25 mg/1
Tablet, film coated	Oral	2.5 mg/1
Tablet, sugar coated	Oral	0.3 mg/1
Tablet, sugar coated	Oral	0.45 mg/1
Tablet, sugar coated	Oral	0.625 mg/1
Tablet, sugar coated	Oral	0.9 mg/1
Tablet, coated	Oral	0.625 mg
Cream	Vaginal	4.0096 g
Cream	Topical; Vaginal	.625 mg / g
Powder, for solution	Intramuscular; Intravenous	25 mg / 5 mL
Powder, for solution	Intramuscular; Intravenous	25 mg / vial
Tablet, sugar coated	Oral	0.3 mg
Tablet	Oral	0.9 mg
Cream	Vaginal	0.625 mg/1g
Cream	Vaginal	0.625 mg / g
Cream	Vaginal	0.625 mg/g
Cream	Vaginal	62.5 mg
Cream	Vaginal	0.0625 g
Tablet	Oral	20.833 mg
Kit	Oral
Kit; tablet; tablet, sugar coated	Oral
Kit; tablet	Oral
Tablet, sugar coated	Oral
Tablet, coated	Oral
Cream	Vaginal	62.500 mg
Granule	Oral	2.5 mg/1
Tablet, sugar coated	Oral	0.625 mg

Prices

Unit description	Cost	Unit
Premarin 0.625 mg/gm Cream 42.5 gm Tube	134.05USD	tube
Premarin 25 mg vial	107.54USD	vial
Premphase 28 0.625-5 mg tablet Disp Pack	69.99USD	disp
Premarin vaginal cream-appl	3.07USD	g
Prempro 0.3 mg-1.5 mg tablet	2.34USD	tablet
Prempro 0.45-1.5 mg tablet	2.34USD	tablet
Prempro 0.625-2.5 mg tablet	2.34USD	tablet
Prempro 0.625-5 mg tablet	2.34USD	tablet
Premarin 0.45 mg tablet	1.97USD	tablet
Premarin 0.9 mg tablet	1.97USD	tablet
Premarin 2.5 mg tablet	1.83USD	tablet
Premarin 2.5 mg Tabs	1.82USD	tablet
Premarin 0.3 mg tablet	1.42USD	tablet
Premarin 0.625 mg tablet	1.42USD	tablet
Premarin 1.25 mg tablet	1.42USD	tablet
Premarin 0.625 mg/g Cream	0.69USD	g
C.E.S. 0.625 mg Tablet	0.11USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5908638	No	1999-06-01	2015-07-26
US5547948	No	1996-08-20	2015-01-17
US5998402	No	1999-12-07	2017-04-04
US6479535	No	2002-11-12	2019-05-06
US7138392	No	2006-11-21	2017-04-04
US7683051	No	2010-03-23	2027-03-10
US8815934	No	2014-08-26	2019-05-06

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	Can range from 173-282 °C depending of the component	Report on carcinogens. 12th edition. NIH.
water solubility	Soluble	'MSDS'
logP	3.7	Hsieh R. et al. 2007. Steroids.
pKa	10	Hurwitz AR. and Liu ST. J Pharm Sci. 1977. (based on the average of different estrogens)

Predicted Properties

Not Available

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.997
Blood Brain Barrier	+	0.9486
Caco-2 permeable	-	0.8738
P-glycoprotein substrate	Non-substrate	0.5295
P-glycoprotein inhibitor I	Non-inhibitor	0.5198
P-glycoprotein inhibitor II	Non-inhibitor	0.9431
Renal organic cation transporter	Non-inhibitor	0.8313
CYP450 2C9 substrate	Non-substrate	0.7886
CYP450 2D6 substrate	Non-substrate	0.8125
CYP450 3A4 substrate	Substrate	0.6454
CYP450 1A2 substrate	Non-inhibitor	0.8152
CYP450 2C9 inhibitor	Non-inhibitor	0.8454
CYP450 2D6 inhibitor	Non-inhibitor	0.9026
CYP450 2C19 inhibitor	Non-inhibitor	0.8017
CYP450 3A4 inhibitor	Non-inhibitor	0.9204
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.8461
Ames test	Non AMES toxic	0.5177
Carcinogenicity	Non-carcinogens	0.5338
Biodegradation	Not ready biodegradable	0.6303
Rat acute toxicity	2.3418 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Strong inhibitor	0.6053
hERG inhibition (predictor II)	Inhibitor	0.7941

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST): Not Available
Spectra: Not Available
Chromatographic Properties: Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Estrogen receptor beta

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560)
Specific Function: DNA binding
Gene Name: ESR2
Uniprot ID: Q92731
Uniprot Name: Estrogen receptor beta
Molecular Weight: 59215.765 Da

References

Cada DJ, Baker DE: Conjugated estrogens and bazedoxifene. Hosp Pharm. 2014 Mar;49(3):273-83. doi: 10.1310/hpj4903-273. [Article]
Ropero AB, Eghbali M, Minosyan TY, Tang G, Toro L, Stefani E: Heart estrogen receptor alpha: distinct membrane and nuclear distribution patterns and regulation by estrogen. J Mol Cell Cardiol. 2006 Sep;41(3):496-510. Epub 2006 Jul 28. [Article]
Stroud FC, Appt SE, Wilson ME, Franke AA, Adams MR, Kaplan JR: Concentrations of isoflavones in macaques consuming standard laboratory monkey diet. J Am Assoc Lab Anim Sci. 2006 Jul;45(4):20-3. [Article]
Hou NN, Zhu YM, Huang HF: [The expression of estrogen receptor alpha and beta in the intervention of different estrogens in rat bone metabolism]. Fen Zi Xi Bao Sheng Wu Xue Bao. 2006 Aug;39(4):289-96. [Article]

Details2. Estrogen receptor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032). Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2) (By similarity)
Specific Function: 14-3-3 protein binding
Gene Name: ESR1
Uniprot ID: P03372
Uniprot Name: Estrogen receptor
Molecular Weight: 66215.45 Da

References

Ropero AB, Eghbali M, Minosyan TY, Tang G, Toro L, Stefani E: Heart estrogen receptor alpha: distinct membrane and nuclear distribution patterns and regulation by estrogen. J Mol Cell Cardiol. 2006 Sep;41(3):496-510. Epub 2006 Jul 28. [Article]
Stroud FC, Appt SE, Wilson ME, Franke AA, Adams MR, Kaplan JR: Concentrations of isoflavones in macaques consuming standard laboratory monkey diet. J Am Assoc Lab Anim Sci. 2006 Jul;45(4):20-3. [Article]
Hou NN, Zhu YM, Huang HF: [The expression of estrogen receptor alpha and beta in the intervention of different estrogens in rat bone metabolism]. Fen Zi Xi Bao Sheng Wu Xue Bao. 2006 Aug;39(4):289-96. [Article]
Gouva L, Tsatsoulis A: The role of estrogens in cardiovascular disease in the aftermath of clinical trials. Hormones (Athens). 2004 Jul-Sep;3(3):171-83. [Article]
Smith MR: Selective estrogen receptor modulators to prevent treatment-related osteoporosis. Rev Urol. 2005;7 Suppl 3:S30-5. [Article]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT: Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98. [Article]
Authors unspecified: Conjugated oestrogens/bazedoxifene. Aust Prescr. 2017 Jun;40(3):114-115. doi: 10.18773/austprescr.2017.039. Epub 2017 May 10. [Article]

Details2. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function: aromatase activity
Gene Name: CYP1A2
Uniprot ID: P05177
Uniprot Name: Cytochrome P450 1A2
Molecular Weight: 58406.915 Da

References

Lin Y, Lu P, Tang C, Mei Q, Sandig G, Rodrigues AD, Rushmore TH, Shou M: Substrate inhibition kinetics for cytochrome P450-catalyzed reactions. Drug Metab Dispos. 2001 Apr;29(4 Pt 1):368-74. [Article]
O'Connell MB, Frye RF, Matzke GR, St Peter JV, Willhite LA, Welch MR, Kowal P, LaValleur J: Effect of conjugated equine estrogens on oxidative metabolism in middle-aged and elderly postmenopausal women. J Clin Pharmacol. 2006 Nov;46(11):1299-307. doi: 10.1177/0091270006292249. [Article]
CTEP CYP1A2 DOCUMENT [File]

Details3. Catechol O-methyltransferase

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol
Specific Function: catechol O-methyltransferase activity
Gene Name: COMT
Uniprot ID: P21964
Uniprot Name: Catechol O-methyltransferase
Molecular Weight: 30036.77 Da

References

Zhu BT, Wu KY, Wang P, Cai MX, Conney AH: O-methylation of catechol estrogens by human placental catechol-o-methyltransferase: interindividual differences in sensitivity to heat inactivation and to inhibition by dietary polyphenols. Drug Metab Dispos. 2010 Oct;38(10):1892-9. doi: 10.1124/dmd.110.033548. Epub 2010 Jul 6. [Article]
Jobe SO, Ramadoss J, Koch JM, Jiang Y, Zheng J, Magness RR: Estradiol-17beta and its cytochrome P450- and catechol-O-methyltransferase-derived metabolites stimulate proliferation in uterine artery endothelial cells: role of estrogen receptor-alpha versus estrogen receptor-beta. Hypertension. 2010 Apr;55(4):1005-11. doi: 10.1161/HYPERTENSIONAHA.109.146399. Epub 2010 Mar 8. [Article]

Carriers

Details1. Thyroxine-binding globulin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inducer

General Function: Major thyroid hormone transport protein in serum
Specific Function: serine-type endopeptidase inhibitor activity
Gene Name: SERPINA7
Uniprot ID: P05543
Uniprot Name: Thyroxine-binding globulin
Molecular Weight: 46324.12 Da

References

CYTOMEL (liothyronine) FDA label [File]

Details2. Sex hormone-binding globulin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration
Specific Function: androgen binding
Gene Name: SHBG
Uniprot ID: P04278
Uniprot Name: Sex hormone-binding globulin
Molecular Weight: 43778.755 Da

References

Cada DJ, Baker DE: Conjugated estrogens and bazedoxifene. Hosp Pharm. 2014 Mar;49(3):273-83. doi: 10.1310/hpj4903-273. [Article]

Details3. Albumin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function: antioxidant activity
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Albumin
Molecular Weight: 69365.94 Da

References

Cada DJ, Baker DE: Conjugated estrogens and bazedoxifene. Hosp Pharm. 2014 Mar;49(3):273-83. doi: 10.1310/hpj4903-273. [Article]

Transporters

Details1. ATP-binding cassette sub-family C member 3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes (PubMed:10359813, PubMed:11581266, PubMed:15083066). Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:11581266, PubMed:15083066). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate) (By similarity). Does not contribute substantially to bile salt physiology but provides an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes (By similarity). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can confer resistance to various anticancer drugs, methotrexate, tenoposide and etoposide, by decreasing accumulation of these drugs in cells (PubMed:10359813, PubMed:11581266)
Specific Function: ABC-type bile acid transporter activity
Gene Name: ABCC3
Uniprot ID: O15438
Uniprot Name: ATP-binding cassette sub-family C member 3
Molecular Weight: 169341.14 Da

References

Hirohashi T, Suzuki H, Sugiyama Y: Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem. 1999 May 21;274(21):15181-5. [Article]

Details2. ATP-binding cassette sub-family C member 4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685)
Specific Function: 15-hydroxyprostaglandin dehydrogenase (NAD+) activity
Gene Name: ABCC4
Uniprot ID: O15439
Uniprot Name: ATP-binding cassette sub-family C member 4
Molecular Weight: 149525.33 Da

References

Zelcer N, Reid G, Wielinga P, Kuil A, van der Heijden I, Schuetz JD, Borst P: Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J. 2003 Apr 15;371(Pt 2):361-7. [Article]

Details3. Multidrug resistance-associated protein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Mediates export of organic anions and drugs from the cytoplasm (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769)
Specific Function: ABC-type glutathione S-conjugate transporter activity
Gene Name: ABCC1
Uniprot ID: P33527
Uniprot Name: Multidrug resistance-associated protein 1
Molecular Weight: 171589.5 Da

References

Qian YM, Song WC, Cui H, Cole SP, Deeley RG: Glutathione stimulates sulfated estrogen transport by multidrug resistance protein 1. J Biol Chem. 2001 Mar 2;276(9):6404-11. Epub 2000 Dec 1. [Article]

Details4. Solute carrier organic anion transporter family member 1A2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1A2
Uniprot ID: P46721
Uniprot Name: Solute carrier organic anion transporter family member 1A2
Molecular Weight: 74144.105 Da

References

Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ: Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther. 2000 Jul;294(1):73-9. [Article]
Kullak-Ublick GA, Fisch T, Oswald M, Hagenbuch B, Meier PJ, Beuers U, Paumgartner G: Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain. FEBS Lett. 1998 Mar 13;424(3):173-6. [Article]
Kanai N, Lu R, Bao Y, Wolkoff AW, Vore M, Schuster VL: Estradiol 17 beta-D-glucuronide is a high-affinity substrate for oatp organic anion transporter. Am J Physiol. 1996 Feb;270(2 Pt 2):F326-31. [Article]
Bossuyt X, Muller M, Hagenbuch B, Meier PJ: Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J Pharmacol Exp Ther. 1996 Mar;276(3):891-6. [Article]
Kontaxi M, Echkardt U, Hagenbuch B, Stieger B, Meier PJ, Petzinger E: Uptake of the mycotoxin ochratoxin A in liver cells occurs via the cloned organic anion transporting polypeptide. J Pharmacol Exp Ther. 1996 Dec;279(3):1507-13. [Article]
Pang KS, Wang PJ, Chung AY, Wolkoff AW: The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein. Hepatology. 1998 Nov;28(5):1341-6. [Article]
Bossuyt X, Muller M, Meier PJ: Multispecific amphipathic substrate transport by an organic anion transporter of human liver. J Hepatol. 1996 Nov;25(5):733-8. [Article]
Hagenbuch B, Adler ID, Schmid TE: Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X. Biochem J. 2000 Jan 1;345 Pt 1:115-20. [Article]
Lee TK, Koh AS, Cui Z, Pierce RH, Ballatori N: N-glycosylation controls functional activity of Oatp1, an organic anion transporter. Am J Physiol Gastrointest Liver Physiol. 2003 Aug;285(2):G371-81. Epub 2003 Apr 17. [Article]
Kouzuki H, Suzuki H, Ito K, Ohashi R, Sugiyama Y: Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes. J Pharmacol Exp Ther. 1999 Feb;288(2):627-34. [Article]
Eckhardt U, Schroeder A, Stieger B, Hochli M, Landmann L, Tynes R, Meier PJ, Hagenbuch B: Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells. Am J Physiol. 1999 Apr;276(4 Pt 1):G1037-42. [Article]

Details5. Hepatic sodium/bile acid cotransporter

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It is strictly dependent on the extracellular presence of sodium (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate (PubMed:14660639, PubMed:34060352). Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321)
Specific Function: bile acid
Gene Name: SLC10A1
Uniprot ID: Q14973
Uniprot Name: Hepatic sodium/bile acid cotransporter
Molecular Weight: 38118.64 Da

References

Schroeder A, Eckhardt U, Stieger B, Tynes R, Schteingart CD, Hofmann AF, Meier PJ, Hagenbuch B: Substrate specificity of the rat liver Na(+)-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells. Am J Physiol. 1998 Feb;274(2 Pt 1):G370-5. [Article]

Details6. Solute carrier family 22 member 10

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Not Available
Specific Function: transmembrane transporter activity
Gene Name: SLC22A10
Uniprot ID: Q63ZE4
Uniprot Name: Solute carrier family 22 member 10
Molecular Weight: 60256.57 Da

References

Youngblood GL, Sweet DH: Identification and functional assessment of the novel murine organic anion transporter Oat5 (Slc22a19) expressed in kidney. Am J Physiol Renal Physiol. 2004 Aug;287(2):F236-44. Epub 2004 Apr 6. [Article]

Details7. Organic anion transporter 3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
Specific Function: organic anion transmembrane transporter activity
Gene Name: SLC22A8
Uniprot ID: Q8TCC7
Uniprot Name: Organic anion transporter 3
Molecular Weight: 59855.585 Da

References

Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M, Terasaki T: Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. J Pharmacol Exp Ther. 2004 Jun;309(3):1273-81. Epub 2004 Feb 4. [Article]
Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS, Hosoya K, Terasaki T: Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40. [Article]
Nagata Y, Kusuhara H, Endou H, Sugiyama Y: Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol. 2002 May;61(5):982-8. [Article]
Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. [Article]
Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK: Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem. 2002 Jul 26;277(30):26934-43. Epub 2002 May 13. [Article]
Kobayashi Y, Ohshiro N, Tsuchiya A, Kohyama N, Ohbayashi M, Yamamoto T: Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab Dispos. 2004 May;32(5):479-83. [Article]
Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. [Article]

Details8. Solute carrier organic anion transporter family member 1C1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones L-thyroxine (T4), L-thyroxine sulfate (T4S), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) at the plasma membrane (PubMed:12351693, PubMed:18566113, PubMed:19129463). Regulates T4 levels in different brain regions by transporting T4, and also by serving as an export pump for T4S, which is a source of T4 after hydrolysis by local sulfatases (PubMed:18566113). Increases the access of these substrates to the intracellular sites where they are metabolized by the deiodinases (PubMed:18566113). Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)), estrone-3-sulfate (E1S) and sulfobromophthalein (BSP) are transported with much lower efficiency (PubMed:12351693, PubMed:19129463). Transports T4 and E1S in a pH-insensitive manner (PubMed:19129463). Facilitates the transport of thyroid hormones across the blood-brain barrier and into glia and neuronal cells in the brain (PubMed:30296914)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1C1
Uniprot ID: Q9NYB5
Uniprot Name: Solute carrier organic anion transporter family member 1C1
Molecular Weight: 78695.625 Da

References

Tohyama K, Kusuhara H, Sugiyama Y: Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier. Endocrinology. 2004 Sep;145(9):4384-91. Epub 2004 May 27. [Article]
Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ: Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol. 2002 Oct;16(10):2283-96. [Article]

Details9. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

Tamai I, Nozawa T, Koshida M, Nezu J, Sai Y, Tsuji A: Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res. 2001 Sep;18(9):1262-9. [Article]
Nozawa T, Tamai I, Sai Y, Nezu J, Tsuji A: Contribution of organic anion transporting polypeptide OATP-C to hepatic elimination of the opioid pentapeptide analogue [D-Ala2, D-Leu5]-enkephalin. J Pharm Pharmacol. 2003 Jul;55(7):1013-20. [Article]
Cui Y, Konig J, Leier I, Buchholz U, Keppler D: Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 2001 Mar 30;276(13):9626-30. Epub 2000 Dec 27. [Article]
Hirano M, Maeda K, Shitara Y, Sugiyama Y: Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004 Oct;311(1):139-46. Epub 2004 May 24. [Article]
Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I: Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos. 2004 Mar;32(3):291-4. [Article]
Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. [Article]
van Montfoort JE, Schmid TE, Adler ID, Meier PJ, Hagenbuch B: Functional characterization of the mouse organic-anion-transporting polypeptide 2. Biochim Biophys Acta. 2002 Aug 19;1564(1):183-8. [Article]
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B: Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33. [Article]

Details10. Solute carrier organic anion transporter family member 2B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Mediates the Na(+)-independent transport of steroid sulfate conjugates and other specific organic anions (PubMed:10873595, PubMed:11159893, PubMed:11932330, PubMed:12724351, PubMed:14610227, PubMed:16908597, PubMed:18501590, PubMed:20507927, PubMed:22201122, PubMed:23531488, PubMed:25132355, PubMed:26383540, PubMed:27576593, PubMed:28408210, PubMed:29871943, PubMed:34628357). Responsible for the transport of estrone 3-sulfate (E1S) through the basal membrane of syncytiotrophoblast, highlighting a potential role in the placental absorption of fetal-derived sulfated steroids including the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S) (PubMed:11932330, PubMed:12409283). Also facilitates the uptake of sulfated steroids at the basal/sinusoidal membrane of hepatocytes, therefore accounting for the major part of organic anions clearance of liver (PubMed:11159893). Mediates the intestinal uptake of sulfated steroids (PubMed:12724351, PubMed:28408210). Mediates the uptake of the neurosteroids DHEA-S and pregnenolone sulfate (PregS) into the endothelial cells of the blood-brain barrier as the first step to enter the brain (PubMed:16908597, PubMed:25132355). Also plays a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May act as a heme transporter that promotes cellular iron availability via heme oxygenase/HMOX2 and independently of TFRC (PubMed:35714613). Also transports heme by-product coproporphyrin III (CPIII), and may be involved in their hepatic disposition (PubMed:26383540). Mediates the uptake of other substrates such as prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, L-thyroxine, leukotriene C4 and thromboxane B2 (PubMed:10873595, PubMed:14610227, PubMed:19129463, PubMed:29871943, Ref.25). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:14610227, PubMed:19129463, PubMed:22201122). The exact transport mechanism has not been yet deciphered but most likely involves an anion exchange, coupling the cellular uptake of organic substrate with the efflux of an anionic compound (PubMed:19129463, PubMed:20507927, PubMed:26277985). Hydrogencarbonate/HCO3(-) acts as a probable counteranion that exchanges for organic anions (PubMed:19129463). Cytoplasmic glutamate may also act as counteranion in the placenta (PubMed:26277985). An inwardly directed proton gradient has also been proposed as the driving force of E1S uptake with a (H(+):E1S) stoichiometry of (1:1) (PubMed:20507927)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO2B1
Uniprot ID: O94956
Uniprot Name: Solute carrier organic anion transporter family member 2B1
Molecular Weight: 76697.93 Da

References

Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B: Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33. [Article]
Tamai I, Nozawa T, Koshida M, Nezu J, Sai Y, Tsuji A: Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res. 2001 Sep;18(9):1262-9. [Article]
Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I: Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther. 2003 Aug;306(2):703-8. Epub 2003 Apr 30. [Article]
Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I: Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004 Feb;308(2):438-45. Epub 2003 Nov 10. [Article]
Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, Sawada Y: Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005 Apr;33(4):518-23. Epub 2005 Jan 7. [Article]

Details11. ATP-dependent translocase ABCB1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. [Article]

Details12. Solute carrier family 22 member 6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
Specific Function: alpha-ketoglutarate transmembrane transporter activity
Gene Name: SLC22A6
Uniprot ID: Q4U2R8
Uniprot Name: Solute carrier family 22 member 6
Molecular Weight: 61815.78 Da

References

Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK: Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem. 2002 Jul 26;277(30):26934-43. Epub 2002 May 13. [Article]

Details13. Organic solute transporter subunit alpha

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols (PubMed:16317684). Able to transport eicosanoids such as prostaglandin E2 (By similarity)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLC51A
Uniprot ID: Q86UW1
Uniprot Name: Organic solute transporter subunit alpha
Molecular Weight: 37734.575 Da

References

Seward DJ, Koh AS, Boyer JL, Ballatori N: Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82. Epub 2003 Apr 28. [Article]

Details14. Organic solute transporter subunit beta

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Modulates SLC51A glycosylation, membrane trafficking and stability activities (PubMed:16317684). The Ost-alpha/Ost-beta complex efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols (PubMed:16317684). Able to transport eicosanoids such as prostaglandin E2 (By similarity)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLC51B
Uniprot ID: Q86UW2
Uniprot Name: Organic solute transporter subunit beta
Molecular Weight: 14346.195 Da

References

Seward DJ, Koh AS, Boyer JL, Ballatori N: Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82. Epub 2003 Apr 28. [Article]

Details15. ATP-binding cassette sub-family C member 2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
Specific Function: ABC-type glutathione S-conjugate transporter activity
Gene Name: ABCC2
Uniprot ID: Q92887
Uniprot Name: ATP-binding cassette sub-family C member 2
Molecular Weight: 174205.64 Da

References

Spears KJ, Ross J, Stenhouse A, Ward CJ, Goh LB, Wolf CR, Morgan P, Ayrton A, Friedberg TH: Directional trans-epithelial transport of organic anions in porcine LLC-PK1 cells that co-express human OATP1B1 (OATP-C) and MRP2. Biochem Pharmacol. 2005 Feb 1;69(3):415-23. Epub 2004 Dec 22. [Article]
Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. [Article]

Details16. Solute carrier organic anion transporter family member 4A1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormones 3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4) and 3,3',5'-triiodo-L-thyronine (rT3), conjugated steroids such as estrone 3-sulfate and estradiol 17-beta glucuronide, bile acids such as taurocholate and prostanoids such as prostaglandin E2, likely operating in a tissue-specific manner (PubMed:10873595, PubMed:19129463, PubMed:30343886). May be involved in uptake of metabolites from the circulation into organs such as kidney, liver or placenta. Possibly drives the selective transport of thyroid hormones and estrogens coupled to an outward glutamate gradient across the microvillous membrane of the placenta (PubMed:30343886). The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable)
Specific Function: organic anion transmembrane transporter activity
Gene Name: SLCO4A1
Uniprot ID: Q96BD0
Uniprot Name: Solute carrier organic anion transporter family member 4A1
Molecular Weight: 77192.505 Da

References

Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A: Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60. [Article]

Details17. ATP-binding cassette sub-family C member 11

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Plays a role in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides, including cAMP and cGMP (PubMed:12764137, PubMed:15537867). Mediates the ATP-dependent efflux of a range of physiological lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates, such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate (PubMed:15537867, PubMed:16359813, PubMed:25896536). Plays a role in the transport of earwax components (PubMed:16444273, PubMed:19383836). Participates in the secretion of odorants and their precursors from the apocrine sweat glands, including the secretion of glutamine conjugates, as well as the Cys-Gly-(S) conjugates of 3-methyl-3-sulfanyl-hexanol (PubMed:19710689). Involved in the cellular extrusion of nucleotide analogs, hence confering resistance to various drugs, including clinically relevant drugs such as 5-fluorouracil (5-FU) and methotrexate (PubMed:12764137, PubMed:15537867, PubMed:25896536)
Specific Function: ABC-type bile acid transporter activity
Gene Name: ABCC11
Uniprot ID: Q96J66
Uniprot Name: ATP-binding cassette sub-family C member 11
Molecular Weight: 154299.625 Da

References

Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD: Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10. [Article]

Details18. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

References

Cui Y, Konig J, Leier I, Buchholz U, Keppler D: Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 2001 Mar 30;276(13):9626-30. Epub 2000 Dec 27. [Article]
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B: Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33. [Article]
Hirano M, Maeda K, Shitara Y, Sugiyama Y: Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004 Oct;311(1):139-46. Epub 2004 May 24. [Article]
Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I: Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos. 2004 Mar;32(3):291-4. [Article]

Details19. Solute carrier family 22 member 11

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds (PubMed:10660625, PubMed:11907186, PubMed:15037815, PubMed:15102942, PubMed:15291761, PubMed:15576633, PubMed:17229912, PubMed:18501590, PubMed:26277985, PubMed:28027879). May be responsible for placental absorption of fetal-derived steroid sulfates such as estrone sulfate (E1S) and the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S), as well as clearing waste products and xenobiotics from the fetus (PubMed:12409283). Maybe also be involved in placental urate homeostasis (PubMed:17229912). Facilitates the renal reabsorption of organic anions such as urate and derived steroid sulfates (PubMed:15037815, PubMed:17229912). Organic anion glutarate acts as conteranion for E1S renal uptake (PubMed:15037815, PubMed:17229912). Possible transport mode may also include DHEA-S/E1S exchange (PubMed:28027879). Also interacts with inorganic anions such as chloride and hydroxyl ions, therefore possible transport modes may include E1S/Cl(-), E1S/OH(-), urate/Cl(-) and urate/OH(-) (PubMed:17229912). Also mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186). Also able to uptake anionic drugs, diuretics, bile salts and ochratoxin A (PubMed:10660625, PubMed:26277985). Mediates the unidirectional efflux of glutamate and aspartate (PubMed:28027879). Glutamate efflux down its transmembrane gradient may drive SLC22A11/OAT4-mediated placental uptake of E1S (PubMed:26277985)
Specific Function: organic anion transmembrane transporter activity
Gene Name: SLC22A11
Uniprot ID: Q9NSA0
Uniprot Name: Solute carrier family 22 member 11
Molecular Weight: 59970.945 Da

References

Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12. [Article]

Details20. Solute carrier organic anion transporter family member 3A1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Putative organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormone L-thyroxine, prostanoids such as prostaglandin E1 and E2, bile acids such as taurocholate, glycolate and glycochenodeoxycholate and peptide hormones such as L-arginine vasopressin, likely operating in a tissue-specific manner (PubMed:10873595, PubMed:14631946, PubMed:16971491, PubMed:19129463, PubMed:30063921). The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable)
Specific Function: organic anion transmembrane transporter activity
Gene Name: SLCO3A1
Uniprot ID: Q9UIG8
Uniprot Name: Solute carrier organic anion transporter family member 3A1
Molecular Weight: 76552.135 Da

References

Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A: Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60. [Article]

Details21. Broad substrate specificity ATP-binding cassette transporter ABCG2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight: 72313.47 Da

References

Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. [Article]
Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y: ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003 Jun 20;278(25):22644-9. Epub 2003 Apr 7. [Article]
Imai Y, Asada S, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y: Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol Pharmacol. 2003 Sep;64(3):610-8. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 11, 2024 18:19

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