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Identification
- Summary
Omaveloxolone is a semisynthetic triterpenoid used to treat Friedreich’s ataxia in adults and adolescents 16 years and older.
- Brand Names
- Skyclarys
- Generic Name
- Omaveloxolone
- DrugBank Accession Number
- DB12513
- Background
Omaveloxolone (RTA-408) is a semisynthetic oleanane triterpenoid with antioxidant and anti-inflammatory properties.2,4 Omaveloxolone acts as an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that mitigates oxidative stress. In patients with Friedreich's ataxia, a genetic disease involving mitochondrial dysfunction, the Nrf2 pathway is impaired, and Nrf2 activity is lower. Therefore, the use of Nrf2 activators such as omaveloxolone represents a therapeutic advantage in this group of patients.1 In February 2023, omaveloxolone was approved by the FDA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.7 The use of omaveloxolone for the treatment of conditions involving mitochondrial dysfunction and oxidative stress has also been evaluated.2,6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Omaveloxolone (DB12513)
- Weight
- Average: 554.723
Monoisotopic: 554.331999611 - Chemical Formula
- C33H44F2N2O3
- Synonyms
- Omaveloxolone
- Propanamide, N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2,2-difluoro-
- External IDs
- RTA 408
- RTA-408
Pharmacology
- Indication
Omaveloxolone is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Friedreich's ataxia •••••••••••• ••••••• - Contraindications & Blackbox Warnings
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The MOXIe study showed that after 4 weeks of administration, the use of omaveloxolone led to robust dose‐dependent changes at 80 ‐300 mg/day.5. The effect of omaveloxolone on QTc interval has yet to be defined.7 The use of omaveloxolone can lead to an elevation in hepatic transaminases (both aspartate transaminase and alanine transaminase) and an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. It can also cause changes in cholesterol.7
- Mechanism of action
The mechanism of action of omaveloxolone has not been fully elucidated; however, its therapeutic effect in patients with Friedreich's ataxia may be linked to its ability to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.7 Nrf2 is a transcription factor that mitigates oxidative stress. In normal conditions, Nrf2 levels are regulated by Kelch-like ECH-associated protein 1 (KEAP1), which binds to Nrf2, prevents Nrf2 translocation to the nucleus, and degrades it by ubiquitination. In the presence of oxidative stress, the ubiquitination system is disrupted. Nrf2 accumulates and translocates to the nucleus, where it promotes the expression of genes against oxidative stress. In patients with Friedreich's ataxia, the Nrf2 signaling pathway is dysfunctional. In Friedreich's ataxia models, Nrf2 has a lower activity; therefore, Nrf2 activators such as omaveloxolone represent a therapeutic opportunity.1 A study has shown that omaveloxolone binds to KEAP1, inhibiting its interaction with Nrf2 and promoting the translocation of Nrf2 to the nucleus.3 Aside from activating Nrf2, omaveloxolone also inhibits the NF-κB signalling pathway, promoting antioxidative, anti-inflammatory, and antiapoptotic mechanisms.2,4
Target Actions Organism ANuclear factor erythroid 2-related factor 2 activatorHumans UKelch-like ECH-associated protein 1 inhibitorHumans - Absorption
Between 50 mg (0.33 times the recommended dosage) and 150 mg, the AUC of omaveloxolone increased in a dose-dependent and dose-proportional manner. However, at the same dose range, the Cmax increased in a less than dose-proportional manner in healthy fasted subjects. The median time to achieve peak plasma concentration was 7 to 14 hours. Compared to fasted conditions, the AUC0-inf and Cmax of omaveloxolone were 350% and 15% higher with a high-fat meal (800 to 1000 calories, with 150, 250, and 500 to 600 calories coming from protein, carbohydrate, and fat, respectively).7
- Volume of distribution
Omaveloxolone has an apparent volume of distribution of 7361 L.7
- Protein binding
The protein binding of omaveloxolone is 97%.7
- Metabolism
Omaveloxolone is mainly metabolized by CYP3A, although CYP2C8 and CYP2J2 play also a minor role.7
- Route of elimination
Omaveloxolone is mainly excreted in feces. In healthy subjects given a single oral dose of radiolabeled omaveloxolone (150 mg), about 92% and 0.1% of the dose were recovered in feces and urine, respectively. Approximately 91% of the omaveloxolone found in feces was recovered within 96 hours after administration.7
- Half-life
Omaveloxolone has a terminal half-life of 57 hours.7
- Clearance
Omaveloxolone has an apparent plasma clearance of 109 L/hr.7
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Toxicity information regarding omaveloxolone is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as elevation in hepatic transaminases and B-Type natriuretic peptide (BNP), as well as lipid abnormalities.7 Symptomatic and supportive measures are recommended.
The carcinogenicity of omaveloxolone has not been evaluated. In a bacterial reverse mutation (Ames) assay, omaveloxolone showed negative results, while a chromosomal aberration assay in human peripheral blood lymphocytes showed positive results. Rats given 0, 1, 3, and 10 mg/kg/day of oral omaveloxolone had a higher incidence of pre- and post-implantation loss and resorptions, leading to a decrease in viable embryos at the highest dose. The no-effect dose (3 mg/kg/day) of omaveloxolone for fertility and reproductive function adverse effects was equivalent to an AUC of approximately 2 times the recommended human dose(150 mg/day).7
- 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 Integrate drug-drug
interactions in your software1,2-Benzodiazepine The serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Omaveloxolone. Abametapir The serum concentration of Omaveloxolone can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be decreased when it is combined with Omaveloxolone. Abiraterone The serum concentration of Abiraterone can be decreased when it is combined with Omaveloxolone. Acalabrutinib The serum concentration of Acalabrutinib can be decreased when it is combined with Omaveloxolone. - Food Interactions
- Take on an empty stomach. Take omaveloxolone capsules on an empty stomach at least 1 hour before eating. Compared to fasting conditions, a high-fat meal increased the Cmax and AUC by approximately 350% and 15%, respectively.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Skyclarys (Reata Pharmaceuticals)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Skyclarys Capsule 50 mg/1 Oral Reata Pharmaceuticals, Inc. 2023-02-28 Not applicable US 
Skyclarys Capsule 50 mg Oral Biogen Netherlands B.V. 2024-07-10 Not applicable EU 
Skyclarys Capsule 50 mg Oral Biogen Netherlands B.V. 2024-07-10 Not applicable EU
Categories
- Drug Categories
- Anti-Inflammatory Agents
- Antioxidants
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C8 Inducers (weak)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (weak)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Substrates
- OAT1/SLC22A6 inhibitors
- Oxidation-Reduction Agent
- Terpenes
- Triterpenes
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as cyclohexenones. These are compounds containing a cylohexenone moiety, which is a six-membered aliphatic ring that carries a ketone and has one endocyclic double bond.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Carbonyl compounds
- Direct Parent
- Cyclohexenones
- Alternative Parents
- Secondary carboxylic acid amides / Nitriles / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides
- Substituents
- Aliphatic homopolycyclic compound / Alkyl fluoride / Alkyl halide / Carbonitrile / Carboxamide group / Carboxylic acid derivative / Cyanide / Cyclohexenone / Hydrocarbon derivative / Nitrile
- Molecular Framework
- Aliphatic homopolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- G69Z98951Q
- CAS number
- 1474034-05-3
- InChI Key
- RJCWBNBKOKFWNY-IDPLTSGASA-N
- InChI
- InChI=1S/C33H44F2N2O3/c1-27(2)11-13-33(37-26(40)32(8,34)35)14-12-31(7)24(20(33)17-27)21(38)15-23-29(5)16-19(18-36)25(39)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3,(H,37,40)/t20-,22-,24-,29-,30+,31+,33-/m0/s1
- IUPAC Name
- N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-4a-yl]-2,2-difluoropropanamide
- SMILES
- CC(F)(F)C(=O)N[C@]12CCC(C)(C)C[C@H]1[C@H]1C(=O)C=C3[C@@]4(C)C=C(C#N)C(=O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
References
- Synthesis Reference
Sheikh, AY et al. (2018). Bardoxolonmethyl-2,2-difluoropropionamide derivatives, polymorphe forms and procedures for use thereof. DK/EP 2989114 T3. Danish Patent and Trademark Office. Available at https://patentimages.storage.googleapis.com/51/87/43/97d0fb3e69ee73/DK2989114T3.pdf
- General References
- Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J: Emerging therapies in Friedreich's Ataxia. Expert Rev Neurother. 2020 Dec;20(12):1215-1228. doi: 10.1080/14737175.2020.1821654. Epub 2020 Sep 21. [Article]
- Jiang Z, Qi G, Lu W, Wang H, Li D, Chen W, Ding L, Yang X, Yuan H, Zeng Q: Omaveloxolone inhibits IL-1beta-induced chondrocyte apoptosis through the Nrf2/ARE and NF-kappaB signalling pathways in vitro and attenuates osteoarthritis in vivo. Front Pharmacol. 2022 Sep 27;13:952950. doi: 10.3389/fphar.2022.952950. eCollection 2022. [Article]
- Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May 1;141(5):1390-1403. doi: 10.1093/brain/awy071. [Article]
- Probst BL, Trevino I, McCauley L, Bumeister R, Dulubova I, Wigley WC, Ferguson DA: RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity. PLoS One. 2015 Apr 21;10(4):e0122942. doi: 10.1371/journal.pone.0122942. eCollection 2015. [Article]
- Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C: Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018 Nov 10;6(1):15-26. doi: 10.1002/acn3.660. eCollection 2019 Jan. [Article]
- Zighan M, Arkadir D, Douiev L, Keller G, Miller C, Saada A: Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects. Front Mol Biosci. 2022 Aug 12;9:890653. doi: 10.3389/fmolb.2022.890653. eCollection 2022. [Article]
- FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
- External Links
- PubChem Compound
- 71811910
- PubChem Substance
- 347828744
- ChemSpider
- 34980948
- 2631931
- ChEMBL
- CHEMBL4303525
- ZINC
- ZINC000144682962
- Wikipedia
- Omaveloxolone
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 Unlock 175K+ rows when you subscribe.View sample data2 Active Not Recruiting Treatment Friedreich's Ataxia 1 somestatus stop reason just information to hide 2 Completed Prevention Breast Cancer 1 somestatus stop reason just information to hide 2 Completed Prevention Cataract Surgery / Endothelial Cell Loss, Corneal / Eye Pain / Ocular Inflammation 1 somestatus stop reason just information to hide 2 Completed Treatment Inflammation and Pain Following Ocular Surgery 1 somestatus stop reason just information to hide 2 Completed Treatment Mitochondrial Myopathies 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 50 mg Capsule Oral 50 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8993640 No 2015-03-31 2033-04-24 US US9670147 No 2017-06-06 2029-04-20 US US8440854 No 2013-05-14 2029-04-20 US US8124799 No 2012-02-28 2029-12-03 US US9701709 No 2017-07-11 2033-04-24 US US11091430 No 2021-08-17 2029-04-20 US US11919838 No 2009-04-20 2029-04-20 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Practically insoluble FDA label pKa 7.26 FDA label - Predicted Properties
Property Value Source Water Solubility 0.00119 mg/mL ALOGPS logP 5.64 ALOGPS logP 6.28 Chemaxon logS -5.7 ALOGPS pKa (Strongest Acidic) 10.11 Chemaxon pKa (Strongest Basic) -5.3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 87.03 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 151.25 m3·mol-1 Chemaxon Polarizability 60.76 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 230.69868 predictedDeepCCS 1.0 (2019) [M+H]+ 232.52602 predictedDeepCCS 1.0 (2019) [M+Na]+ 238.58678 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Activator
- General Function
- Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles (PubMed:11035812, PubMed:19489739, PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:11035812, PubMed:15601839, PubMed:29018201). In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed:19489739, PubMed:29590092). The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes (PubMed:20452972). May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region (PubMed:7937919). Also plays an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (By similarity). Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (By similarity). Binds to the proximity of pro-inflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the NRF2-binding motif and reactive oxygen species level (By similarity). Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses (PubMed:30158636). Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism (PubMed:33009401)
- Specific Function
- Dna binding
- Gene Name
- NFE2L2
- Uniprot ID
- Q16236
- Uniprot Name
- Nuclear factor erythroid 2-related factor 2
- Molecular Weight
- 67825.9 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- By binding and inhibiting KEAP1, omaveloxolone activates nuclear factor erythroid 2-related factor 2 (Nrf2).
- General Function
- Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:37339955). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835)
- Specific Function
- Disordered domain specific binding
- Gene Name
- KEAP1
- Uniprot ID
- Q14145
- Uniprot Name
- Kelch-like ECH-associated protein 1
- Molecular Weight
- 69665.765 Da
References
- Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May 1;141(5):1390-1403. doi: 10.1093/brain/awy071. [Article]
- Parsons ALM, Bucknor EMV, Castroflorio E, Soares TR, Oliver PL, Rial D: The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy. Antioxidants (Basel). 2022 Jan 14;11(1):157. doi: 10.3390/antiox11010157. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- 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
- FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). 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:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- Arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) in the cardiovascular system (PubMed:19965576, PubMed:8631948). 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:19965576, PubMed:8631948). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:8631948). Converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EpETrE), likely playing a major role in the epoxidation of endogenous cardiac arachidonic acid pools (PubMed:8631948). In endothelial cells, participates in eicosanoids metabolism by converting hydroperoxide species into hydroxy epoxy metabolites. In combination with 15-lipoxygenase metabolizes arachidonic acid and converts hydroperoxyicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs), which are precursors of vasodilatory trihydroxyicosatrienoic acids (THETAs). This hydroperoxide isomerase activity is NADPH- and O2-independent (PubMed:19737933). Catalyzes the monooxygenation of a various xenobiotics, such as danazol, amiodarone, terfenadine, astemizole, thioridazine, tamoxifen, cyclosporin A and nabumetone (PubMed:19923256). Catalyzes hydroxylation of the anthelmintics albendazole and fenbendazole (PubMed:23959307). Catalyzes the sulfoxidation of fenbedazole (PubMed:19923256)
- Specific Function
- Arachidonic acid 11,12-epoxygenase activity
- Gene Name
- CYP2J2
- Uniprot ID
- P51589
- Uniprot Name
- Cytochrome P450 2J2
- Molecular Weight
- 57610.165 Da
References
- FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
Drug created at October 20, 2016 22:40 / Updated at August 26, 2024 19:21