Cholecystokinin

Overview

DrugBank ID
DB08862
Type
Small Molecule
US Approved
NO
Other Approved
YES
Clinical Trials
Phase 0
0
Phase 1
1
Phase 2
0
Phase 3
0
Phase 4
1
Mechanism of Action

Identification

Generic Name
Cholecystokinin
DrugBank Accession Number
DB08862
Background

Cholecystokinin ( also known as CCK or CCK-PZ) is a peptide hormone of the gastrointestinal system which is responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum (the first portion of the small intestine) and leads to the release of bile and digestive enzymes. CCK also acts as an appetite suppressant and has been studied for weight management regimens 12.

Normally, it is an endogenous hormone but is available commercially for diagnostic processes and replacement in pancreatic insufficiency 21,22,23. in the octapeptide form.

Cholecystokinin is one of the first gastrointestinal hormones discovered, identified more than 90 years ago due to its ability to stimulate gallbladder contraction in 1928. Soon after, it was recognized to be identical to the factor responsible for stimulating pancreatic exocrine secretion in 1943 11. This hormone has also been shown to have positive effects on enteric smooth muscle contraction and on nerve activity at multiple locations in the peripheral and central nervous system. In addition to its roles in promoting smooth muscle cell contraction/exocrine cell secretion, CCK promotes cell growth, energy production, gene expression and protein synthesis, processes that have profound for drug development 11. This drug has also been investigated for possible antipsychotic properties, owing to its effect on CCK receptors in the brain 13.

Recent studies have suggested that cholecystokinin also plays a major role in inducing drug tolerance to opioids such as morphine and heroin, and is partially implicated in experiences of pain hypersensitivity during opioid withdrawal 1.

Type
Small Molecule
Groups
Approved, Investigational
Synonyms
  • CCK-PZ
  • Human CCK-33
  • Human cholecystokinin-33
  • Pancreozymin

Pharmacology

Indication

For use as a diagnostic aid for evaluation of gallbladder disorders. It is also used in conjunction with secretin in pancreatic insufficiency 9.

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Pharmacodynamics

Cholecystokinin (CCK) plays an imperative role in facilitating digestion within the small intestine. The activation of the CCK1 receptor by CCK has demonstrated to be responsible for a wide variety of important physiologic functions, including the stimulation of gallbladder, contraction and exocrine pancreatic enzyme secretion, delay of gastric emptying, relaxation of the sphincter of Oddi, inhibition of gastric acid secretion, and induction of satiety 7,22. Cholecystokinin is also produced by neurons in the enteric nervous system and is found to be widely distributed in the brain 7. An interesting function of CCK is the role it plays in stimulating the CCK receptor and subsequently regulating food consumption, which may prove to be a highly useful treatment for obesity 14. Exogenous administration CCK has been widely studied 16.

Diseases resulting from excessive or deficient secretion of cholecystokinin are rare. Cholecystokinin deficiency has been described in humans as part of autoimmune polyglandular syndrome, characterized as a malabsorption syndrome clinically similar to pancreatic exocrine insufficiency. Additionally, there is increasing evidence that alterations in expression of cholecystokinin or its receptor within the brain may possibly play a role in the pathogenesis of various types of anxiety disorders and schizophrenia 7.

Foodstuffs flowing into the small intestine are mostly made up of large macromolecules (proteins, polysaccharides, and triglyceride) that require digestion into small molecules (amino acids, monosaccharides, fatty acids) in order to be absorbed. Digestive enzymes from the pancreas and bile salts from the liver (which are stored in the gallbladder) are necessary for digestion. Cholecystokinin is the primary stimulus for the release of pancreatic enzymes and bile secretion into the small intestine. Additionally, cholecystokinin, induces contraction of the gallbladder muscle, resulting in the reduction of gallbladder size and evacuation of bile 9.

Mechanism of action

Cholecystokinin (CCK) is a peptide hormone discovered in the small intestine. Together with secretin and gastrin, CCK constitutes the classical gut hormone triad. In addition to gallbladder contraction, CCK also regulates pancreatic enzyme secretion and growth, intestinal motility, satiety signaling and the inhibition of gastric acid secretion. CCK is, however, also a transmitter in central and intestinal neurons. Notably, CCK is the most ubiquitously found neuropeptide in the human brain. Owing to difficulties in developing accurate assays for the hormone, knowledge about CCK secretion in disease is limited. Available data indicate, however, that proCCK is expressed in certain malignant neuroendocrine tumors and sarcomas, whereas the secretion of CCK is affected in celiac disease and the eating disorder bulimia nervosa. Stimulation with exogenous CCK has proved this protein useful in diagnostic imaging of gallbladder and pancreatic diseases, as well as testing of medullary thyroid carcinomas 2,6,18.

Cholecystokinin, a natural polypeptide which is formed in the amine precursor uptake and decarboxylation (APUD) cells of the proximal mucosa of the small intestine, promotes contraction of the gallbladder muscle, resulting in the reduction of gallbladder size and the expression of bile 9. Cholecystokinin stimulates secretion of pancreatic digestive enzymes and secretion from the glands of Brunner 9.

CCK is composed of a five amino acid sequence at the carboxyl terminus that is identical to that of gastrin. The carboxyl terminus confers the biologic activity of CCK; as a result, gastrin has CCK-mimicking activity and CCK has gastrin-mimicking activity. The amino acid sequence similarity has made the creation of assays for CCK cumbersome, due to the fact that antibodies specific for the biologically active portion the molecule often cross-react with gastrin. This hormone circulates in the blood at concentrations 10 to 100 times greater than that of CCK 14.

TargetActionsOrganism
ACholecystokinin receptor type A
agonist
Humans
URAF proto-oncogene serine/threonine-protein kinase
agonist
Humans
UMitogen-activated protein kinase 3Not AvailableHumans
UPro-epidermal growth factorNot AvailableHumans
UProtein kinase C beta type
agonist
Humans
UGastrin/cholecystokinin type B receptor
agonist
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

2.5 min 17

Clearance

Not Available

Adverse Effects
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Toxicity

Ld 50 in rats : 2730 mg/kg (oral) 24.

Cholecystokinin has been associated with increased anxiety and panic attacks 5.

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.
DrugInteraction
AcetylcysteineThe excretion of Cholecystokinin can be decreased when combined with Acetylcysteine.
AmbrisentanThe excretion of Ambrisentan can be decreased when combined with Cholecystokinin.
AmprenavirThe excretion of Cholecystokinin can be decreased when combined with Amprenavir.
ApalutamideThe serum concentration of Cholecystokinin can be decreased when it is combined with Apalutamide.
AsunaprevirThe excretion of Asunaprevir can be decreased when combined with Cholecystokinin.
Food Interactions
Not Available

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Cholecystokinin Inj 75unit/vialPowder, for solution75 unit / vialIntravenousFerring Pharmaceuticals1990-12-311999-08-04Canada flag

Categories

ATC Codes
V04CK02 — Pancreozymin (cholecystokinin)
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
00XI8W60QF
CAS number
9011-97-6
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

References

General References
  1. Romanelli L, Morrone LA, Amico MC, Palmery M, Tucci P, Valeri P: Inhibitory control of the acute mu-withdrawal response by indirectly activated adenosine A1 and kappa-opioid systems in the Guinea-pig ileum; reversal by cholecystokinin. Neurotoxicology. 2005 Oct;26(5):829-39. doi: 10.1016/j.neuro.2005.02.001. [Article]
  2. Rehfeld JF: Clinical endocrinology and metabolism. Cholecystokinin. Best Pract Res Clin Endocrinol Metab. 2004 Dec;18(4):569-86. doi: 10.1016/j.beem.2004.07.002. [Article]
  3. Williams JA: Mechanism of action of cholecystokinin: a not atypical brain-gut peptide. Nihon Naibunpi Gakkai Zasshi. 1985 May 20;61(5):533-40. [Article]
  4. Hoffmann P, Eberlein GA, Reeve JR Jr, Bunte RH, Grandt D, Goebell H, Eysselein VE: Comparison of clearance and metabolism of infused cholecystokinins 8 and 58 in dogs. Gastroenterology. 1993 Dec;105(6):1732-6. [Article]
  5. Bradwejn J, Koszycki D: Cholecystokinin and panic disorder: past and future clinical research strategies. Scand J Clin Lab Invest Suppl. 2001;234:19-27. [Article]
  6. Kwekkeboom DJ, Bakker WH, Kooij PP, Erion J, Srinivasan A, de Jong M, Reubi JC, Krenning EP: Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med. 2000 Sep;27(9):1312-7. [Article]
  7. cholecystokinin [Link]
  8. Cholecystokinin metabolism in man and dogs [Link]
  9. Cholecystokinin [Link]
  10. Cholecystokinin- a review [Link]
  11. Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor [Link]
  12. Cholecystokinin receptors in brain: Effects of obesity, drug treatment, and lesions Author links open overlay panel [Link]
  13. SR146131, a cholecystokinin-A receptor agonist, antagonizes prepulse inhibition deficits produced by dizocilpine and DOI [Link]
  14. Physiology of CCK [Link]
  15. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
  16. Effect of Exogenous Cholecystokinin (CCK)-8 on Food Intake and Plasma CCK, Leptin, and Insulin Concentrations in Older and Young Adults: Evidence for Increased CCK Activity as a Cause of the Anorexia of Aging [Link]
  17. Comparison of Gallbladder Function Obtained with Regular CCK-8 and Pharmacy-Compounded CCK-8 [Link]
  18. Bioactivity of synthetic human cholecystokinin (CCK)-33 in vitro and in vivo [Link]
  19. Cholecystokinin Octapeptide [Link]
  20. Cholecystokinin Octapeptide, [125I]-, Bolton-Hunter Labeled, 10µCi [Link]
  21. Alfa Aesar™ Cholecystokinin, CCK Octapeptide (26-33) [Link]
  22. Cholecystokinin-Pancreozymin Peptides Products [Link]
  23. CCK Octapeptide sulfated [Link]
  24. Cholecystokinin Octapeptide [Link]
PubChem Substance
347910375
RxNav
2420
Wikipedia
Cholecystokinin

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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedBasic ScienceType 2 Diabetes Mellitus2somestatusstop reasonjust information to hide
4CompletedDiagnosticAbdominal Pain1somestatusstop reasonjust information to hide
1RecruitingTreatmentNeuroendocrine Tumor GEP Grade 1-3 / Neuroendocrine Tumor of the Lung Grade 1 and 2 / Neuroendocrine Tumor of the Thymus Grade 1 and 2 / Thyroid Gland Medullary Carcinoma1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionIntravenous75 unit / vial
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)75http://www.perkinelmer.com/Content/MSDSDatabase/CHOLECYSTOKININ%20OCTAPEPTIDE%20125I-BOLTON-HUNTER%20LABELED%20ASP1%20CCK-8-MSDS_US-English.pdf
water solubilitynot water solublehttp://www.perkinelmer.com/Content/MSDSDatabase/CHOLECYSTOKININ%20OCTAPEPTIDE%20125I-BOLTON-HUNTER%20LABELED%20ASP1%20CCK-8-MSDS_US-English.pdf
Predicted Properties
Not Available
Predicted ADMET Features
Not Available

Spectra

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

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor for cholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gastrin. It modulates feeding and dopamine-induced behavior in the central and peripheral nervous system. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
Specific Function
cholecystokinin receptor activity
Gene Name
CCKAR
Uniprot ID
P32238
Uniprot Name
Cholecystokinin receptor type A
Molecular Weight
47840.645 Da
References
  1. Williams JA: Mechanism of action of cholecystokinin: a not atypical brain-gut peptide. Nihon Naibunpi Gakkai Zasshi. 1985 May 20;61(5):533-40. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation
Specific Function
ATP binding
Gene Name
RAF1
Uniprot ID
P04049
Uniprot Name
RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight
73051.025 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway (PubMed:34497368). MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade also plays a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DEPTOR, FRS2 or GRB10) (PubMed:35216969). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade
Specific Function
ATP binding
Gene Name
MAPK3
Uniprot ID
P27361
Uniprot Name
Mitogen-activated protein kinase 3
Molecular Weight
43135.16 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6. Can induce neurite outgrowth in motoneurons of the pond snail Lymnaea stagnalis in vitro (PubMed:10964941)
Specific Function
calcium ion binding
Gene Name
EGF
Uniprot ID
P01133
Uniprot Name
Pro-epidermal growth factor
Molecular Weight
133993.12 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity (PubMed:11598012). Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A (PubMed:20228790). In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1-MAPK/ERK signaling cascade. Participates in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Phosphorylates SLC2A1/GLUT1, promoting glucose uptake by SLC2A1/GLUT1 (PubMed:25982116). Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription (PubMed:19176525). Phosphorylates KLHL3 in response to angiotensin II signaling, decreasing the interaction between KLHL3 and WNK4 (PubMed:25313067). Phosphorylates and activates LRRK1, which phosphorylates RAB proteins involved in intracellular trafficking (PubMed:36040231)
Specific Function
ATP binding
Gene Name
PRKCB
Uniprot ID
P05771
Uniprot Name
Protein kinase C beta type
Molecular Weight
76868.45 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Receptor for gastrin and cholecystokinin. The CCK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
Specific Function
1-phosphatidylinositol-3-kinase regulator activity
Gene Name
CCKBR
Uniprot ID
P32239
Uniprot Name
Gastrin/cholecystokinin type B receptor
Molecular Weight
48418.51 Da

Transporters

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
  1. Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA: Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology. 2001 Nov;121(5):1185-90. [Article]
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
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [Article]

Drug created at March 04, 2013 00:52 / Updated at October 09, 2024 11:18