Metyrapone
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Identification
- Summary
Metyrapone is a steroid 11-beta-monooxygenase inhibitor used to test hypothalamic-pituitary ACTH function.
- Brand Names
- Metopirone
- Generic Name
- Metyrapone
- DrugBank Accession Number
- DB01011
- Background
An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of cushing syndrome.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 226.2738
Monoisotopic: 226.11061308 - Chemical Formula
- C14H14N2O
- Synonyms
- Metirapona
- Metyrapone
- Métyrapone
- Metyraponum
Pharmacology
- Indication
Used as a diagnostic drug for testing hypothalamic-pituitary ACTH function. Occasionally used in Cushing's syndrome.
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- Pharmacodynamics
Metopirone is an inhibitor of endogenous adrenal corticosteroid synthesis.
- Mechanism of action
The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-ß-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.
Target Actions Organism ACytochrome P450 11B1, mitochondrial inhibitorHumans UCamphor 5-monooxygenase other/unknownPseudomonas putida - Absorption
Absorbed rapidly and well when administered orally. Peak plasma concentrations are usually reached 1 hour after administration.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
Hepatic. The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Metyrapone and metyrapol are both conjugated with glucuronide.
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- Route of elimination
After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.
- Half-life
1.9 ±0.7 hours.
- Clearance
Not Available
- 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
Oral LD50 in rats is 521 mg/kg. One case has been recorded in which a 6-year-old girl died after two doses of Metopirone, 2 g. Symptoms of overdose include cardiac arrhythmias, hypotension, dehydration, anxiety, confusion, weakness, impairment of consciousness, nausea, vomiting, epigastric pain, and diarrhea.
- 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 softwareAbacavir Metyrapone may decrease the excretion rate of Abacavir which could result in a higher serum level. Abemaciclib The metabolism of Abemaciclib can be increased when combined with Metyrapone. Acalabrutinib The metabolism of Acalabrutinib can be increased when combined with Metyrapone. Aceclofenac Aceclofenac may decrease the excretion rate of Metyrapone which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Metyrapone which could result in a higher serum level. - Food Interactions
- Take with food. Take metyrapone with milk or a snack according to the specific instructions for a single or multi-dose test.
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
- Metopiron
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Metopirone Capsule, gelatin coated 250 mg/1 Oral Novartis Pharmaceuticals Corporation 2006-01-04 2006-01-04 US Metopirone Capsule, gelatin coated 250 mg/1 Oral Novartis 1962-01-25 2012-11-30 US Metopirone Capsule, gelatin coated 250 mg/1 Oral HRA Pharma Rare Diseases 1962-01-25 Not applicable US
Categories
- ATC Codes
- V04CD01 — Metyrapone
- Drug Categories
- Cytochrome P-450 CYP2A6 Inhibitors
- Cytochrome P-450 CYP2A6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2E1 Inhibitors
- Cytochrome P-450 CYP2E1 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Diagnostic Agents
- Drugs that are Mainly Renally Excreted
- Enzyme Inhibitors
- Noxae
- Pyridines
- Steroid Synthesis Inhibitors
- Tests for Pituitary Function
- Toxic Actions
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as aryl alkyl ketones. These are ketones have the generic structure RC(=O)R', where R = aryl group and R'=alkyl group.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Carbonyl compounds
- Direct Parent
- Aryl alkyl ketones
- Alternative Parents
- Pyridines and derivatives / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
- Substituents
- Aromatic heteromonocyclic compound / Aryl alkyl ketone / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organoheterocyclic compound / Organonitrogen compound / Organopnictogen compound
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- aromatic ketone (CHEBI:44241) / a small molecule (CPD-7023)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- ZS9KD92H6V
- CAS number
- 54-36-4
- InChI Key
- FJLBFSROUSIWMA-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H14N2O/c1-14(2,12-6-4-8-16-10-12)13(17)11-5-3-7-15-9-11/h3-10H,1-2H3
- IUPAC Name
- 2-methyl-1,2-bis(pyridin-3-yl)propan-1-one
- SMILES
- CC(C)(C(=O)C1=CN=CC=C1)C1=CC=CN=C1
References
- General References
- Not Available
- External Links
- Human Metabolome Database
- HMDB0015146
- KEGG Drug
- D00410
- KEGG Compound
- C07205
- PubChem Compound
- 4174
- PubChem Substance
- 46504862
- ChemSpider
- 4030
- BindingDB
- 50028166
- 6923
- ChEBI
- 44241
- ChEMBL
- CHEMBL934
- ZINC
- ZINC000000001728
- Therapeutic Targets Database
- DAP000424
- PharmGKB
- PA450486
- PDBe Ligand
- MYT
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Metyrapone
- PDB Entries
- 1phg / 1w0g / 4zf8 / 6ma6 / 7e7f
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 dataNot Available Completed Treatment Dependence, Cocaine 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Other Glucocorticoid Treatment / Overeating / Overweight and Obesity 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Hypercortisolism 1 somestatus stop reason just information to hide Not Available Unknown Status Not Available Brain Injury / Craniocerebral Injuries 1 somestatus stop reason just information to hide 4 Unknown Status Treatment Depressive Disorder / Hormone Disturbance 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Novartis pharmaceuticals corp
- Packagers
- Novartis AG
- R.P. Scherer GmbH and Co. KG
- Dosage Forms
Form Route Strength Capsule Oral 250 MG Capsule, gelatin coated Oral 250 mg/1 - Prices
Unit description Cost Unit Metopirone 250 mg capsule 3.39USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 50.5 °C PhysProp water solubility Sparingly soluble Not Available logP 1.8 Not Available - Predicted Properties
Property Value Source Water Solubility 0.427 mg/mL ALOGPS logP 2.09 ALOGPS logP 2.03 Chemaxon logS -2.7 ALOGPS pKa (Strongest Basic) 4.87 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 42.85 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 65.94 m3·mol-1 Chemaxon Polarizability 23.98 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9872 Blood Brain Barrier + 0.985 Caco-2 permeable + 0.7108 P-glycoprotein substrate Non-substrate 0.6099 P-glycoprotein inhibitor I Non-inhibitor 0.6787 P-glycoprotein inhibitor II Non-inhibitor 0.9579 Renal organic cation transporter Non-inhibitor 0.8039 CYP450 2C9 substrate Non-substrate 0.8174 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.6282 CYP450 1A2 substrate Inhibitor 0.9107 CYP450 2C9 inhibitor Non-inhibitor 0.9071 CYP450 2D6 inhibitor Non-inhibitor 0.9484 CYP450 2C19 inhibitor Non-inhibitor 0.9026 CYP450 3A4 inhibitor Inhibitor 0.7959 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5382 Ames test Non AMES toxic 0.907 Carcinogenicity Non-carcinogens 0.8616 Biodegradation Not ready biodegradable 0.9518 Rat acute toxicity 2.6066 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9786 hERG inhibition (predictor II) Non-inhibitor 0.8202
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 160.5717056 predictedDarkChem Lite v0.1.0 [M-H]- 159.7210056 predictedDarkChem Lite v0.1.0 [M-H]- 156.25461 predictedDeepCCS 1.0 (2019) [M+H]+ 160.9069056 predictedDarkChem Lite v0.1.0 [M+H]+ 160.4763056 predictedDarkChem Lite v0.1.0 [M+H]+ 158.61261 predictedDeepCCS 1.0 (2019) [M+Na]+ 160.4450056 predictedDarkChem Lite v0.1.0 [M+Na]+ 159.8473056 predictedDarkChem Lite v0.1.0 [M+Na]+ 164.70576 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Catalyzes a variety of reactions that are essential for many species, including detoxification, defense, and the formation of endogenous chemicals like steroid hormones. Steroid 11beta, 18- and 19-hydroxylase with preferred regioselectivity at 11beta, then 18, and lastly 19 (By similarity). Catalyzes the hydroxylation of 11-deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at 11beta position, yielding cortisol or corticosterone, respectively, but cannot produce aldosterone (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate for hydroxylation and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:18215163). Due to its lack of 18-oxidation activity, it is incapable of generating aldosterone (PubMed:23322723). Could also be involved in the androgen metabolic pathway (Probable).
- Specific Function
- corticosterone 18-monooxygenase activity
- Gene Name
- CYP11B1
- Uniprot ID
- P15538
- Uniprot Name
- Cytochrome P450 11B1, mitochondrial
- Molecular Weight
- 57572.44 Da
References
- Young EA, Ribeiro SC, Ye W: Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression. Psychoneuroendocrinology. 2007 Jun;32(5):503-7. Epub 2007 Apr 25. [Article]
- Johansson MK, Sanderson JT, Lund BO: Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro. 2002 Apr;16(2):113-21. [Article]
- Hermansson V, Asp V, Bergman A, Bergstrom U, Brandt I: Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p'-DDD in Y-1 adrenal cells. Arch Toxicol. 2007 Nov;81(11):793-801. Epub 2007 May 9. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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
- Pseudomonas putida
- Pharmacological action
- Unknown
- Actions
- Other/unknown
- General Function
- Involved in a camphor oxidation system.
- Specific Function
- camphor 5-monooxygenase activity
- Gene Name
- camC
- Uniprot ID
- P00183
- Uniprot Name
- Camphor 5-monooxygenase
- Molecular Weight
- 46668.8 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
- Bistolas N, Christenson A, Ruzgas T, Jung C, Scheller FW, Wollenberger U: Spectroelectrochemistry of cytochrome P450cam. Biochem Biophys Res Commun. 2004 Feb 13;314(3):810-6. [Article]
- Shiro Y, Fujii M, Isogai Y, Adachi S, Iizuka T, Obayashi E, Makino R, Nakahara K, Shoun H: Iron-ligand structure and iron redox property of nitric oxide reductase cytochrome P450nor from Fusarium oxysporum: relevance to its NO reduction activity. Biochemistry. 1995 Jul 18;34(28):9052-8. [Article]
- Schunemann V, Jung C, Terner J, Trautwein AX, Weiss R: Spectroscopic studies of peroxyacetic acid reaction intermediates of cytochrome P450cam and chloroperoxidase. J Inorg Biochem. 2002 Sep 20;91(4):586-96. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Catalyzes a variety of reactions that are essential for many species, including detoxification, defense, and the formation of endogenous chemicals like steroid hormones. Steroid 11beta, 18- and 19-hydroxylase with preferred regioselectivity at 11beta, then 18, and lastly 19 (By similarity). Catalyzes the hydroxylation of 11-deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at 11beta position, yielding cortisol or corticosterone, respectively, but cannot produce aldosterone (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate for hydroxylation and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:18215163). Due to its lack of 18-oxidation activity, it is incapable of generating aldosterone (PubMed:23322723). Could also be involved in the androgen metabolic pathway (Probable).
- Specific Function
- corticosterone 18-monooxygenase activity
- Gene Name
- CYP11B1
- Uniprot ID
- P15538
- Uniprot Name
- Cytochrome P450 11B1, mitochondrial
- Molecular Weight
- 57572.44 Da
References
- Johansson MK, Sanderson JT, Lund BO: Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro. 2002 Apr;16(2):113-21. [Article]
- Denner K, Vogel R, Schmalix W, Doehmer J, Bernhardt R: Cloning and stable expression of the human mitochondrial cytochrome P45011B1 cDNA in V79 Chinese hamster cells and their application for testing of potential inhibitors. Pharmacogenetics. 1995 Apr;5(2):89-96. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). 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:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable).
- Specific Function
- 4-nitrophenol 2-monooxygenase activity
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
- Heit C, Dong H, Chen Y, Thompson DC, Deitrich RA, Vasiliou VK: The role of CYP2E1 in alcohol metabolism and sensitivity in the central nervous system. Subcell Biochem. 2013;67:235-47. doi: 10.1007/978-94-007-5881-0_8. [Article]
- Montoliu C, Valles S, Renau-Piqueras J, Guerri C: Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J Neurochem. 1994 Nov;63(5):1855-62. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase that catalyzes the biosynthesis of aldosterone, the main mineralocorticoid in the human body responsible for salt and water homeostasis, thus involved in blood pressure regulation, arterial hypertension, and the development of heart failure (PubMed:11856349, PubMed:12530636, PubMed:1518866, PubMed:15356073, PubMed:1594605, PubMed:1775135, PubMed:22446688, PubMed:23322723, PubMed:9814482, PubMed:9814506). Catalyzes three sequential oxidative reactions of 11-deoxycorticosterone (21-hydroxyprogesterone), namely 11-beta hydroxylation, followed by two successive oxidations at C18 yielding 18-hydroxy and then 18-oxo intermediates (that would not leave the enzyme active site during the consecutive hydroxylation reactions), ending with the formation of aldosterone (PubMed:11856349, PubMed:12530636, PubMed:1518866, PubMed:1594605, PubMed:1775135, PubMed:22446688, PubMed:23322723, PubMed:9814506). Can also produce 18-hydroxycortisol and 18-oxocortisol, derived from successive oxidations of cortisol at C18, normally found at very low levels, but significantly increased in primary aldosteronism, the most common form of secondary hypertension (PubMed:15356073, PubMed:9814482). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:11856349, PubMed:1594605, PubMed:23322723, PubMed:9814506). Could also be involved in the androgen metabolic pathway (Probable).
- Specific Function
- corticosterone 18-monooxygenase activity
- Gene Name
- CYP11B2
- Uniprot ID
- P19099
- Uniprot Name
- Cytochrome P450 11B2, mitochondrial
- Molecular Weight
- 57559.62 Da
References
- Roumen L, Sanders MP, Pieterse K, Hilbers PA, Plate R, Custers E, de Gooyer M, Smits JF, Beugels I, Emmen J, Ottenheijm HC, Leysen D, Hermans JJ: Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics. J Comput Aided Mol Des. 2007 Aug;21(8):455-71. Epub 2007 Jul 24. [Article]
- Gomez-Sanchez CE, Zhou MY, Cozza EN, Morita H, Foecking MF, Gomez-Sanchez EP: Aldosterone biosynthesis in the rat brain. Endocrinology. 1997 Aug;138(8):3369-73. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2A6
- Uniprot ID
- P11509
- Uniprot Name
- Cytochrome P450 2A6
- Molecular Weight
- 56517.005 Da
References
- Pelkonen O, Sotaniemi EA, Ahokas JT: Coumarin 7-hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons. Br J Clin Pharmacol. 1985 Jan;19(1):59-66. doi: 10.1111/j.1365-2125.1985.tb02613.x. [Article]
- Liu C, Zhuo X, Gonzalez FJ, Ding X: Baculovirus-mediated expression and characterization of rat CYP2A3 and human CYP2a6: role in metabolic activation of nasal toxicants. Mol Pharmacol. 1996 Oct;50(4):781-8. [Article]
- Draper AJ, Madan A, Parkinson A: Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Arch Biochem Biophys. 1997 May 1;341(1):47-61. doi: 10.1006/abbi.1997.9964. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- 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
- Brandon EF, Meijerman I, Klijn JS, den Arend D, Sparidans RW, Lazaro LL, Beijnen JH, Schellens JH: In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction. Anticancer Drugs. 2005 Oct;16(9):935-43. [Article]
- Sevrioukova I: Interaction of Human Drug-Metabolizing CYP3A4 with Small Inhibitory Molecules. Biochemistry. 2019 Feb 19;58(7):930-939. doi: 10.1021/acs.biochem.8b01221. Epub 2019 Jan 24. [Article]
- Harvey JL, Paine AJ, Maurel P, Wright MC: Effect of the adrenal 11-beta-hydroxylase inhibitor metyrapone on human hepatic cytochrome P-450 expression: induction of cytochrome P-450 3A4. Drug Metab Dispos. 2000 Jan;28(1):96-101. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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
- Teng S, Jekerle V, Piquette-Miller M: Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos. 2003 Nov;31(11):1296-9. [Article]
Drug created at June 13, 2005 13:24 / Updated at June 02, 2024 21:48