Methimazole (original) (raw)

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Description

A medication used to treat an overactive thyroid.

Description

A medication used to treat an overactive thyroid.

DrugBank ID

DB00763

Type

Small Molecule

US Approved

YES

Other Approved

YES

Therapeutic Categories

• Antithyroid agents
• Thyroid Hormone Synthesis Inhibitor

Mechanism of Action

• Thyroid peroxidase
  Substrate
  Inhibitor

Summary

Methimazole is a thionamide antithyroid agent that inhibits the actions of thyroid peroxidase, leading to a reduction in thyroid hormone synthesis and amelioration of hyperthyroidism.

Brand Names

Tapazole

Generic Name

Methimazole

DrugBank Accession Number

DB00763

Background

Methimazole is a thionamide antithyroid agent that inhibits the synthesis of thyroid hormones.6,14,12 It was first introduced as an antithyroid agent in 19492 and is now commonly used in the management of hyperthyroidism, particularly in those for whom more aggressive options such as surgery or radioactive iodine therapy are inappropriate.18,19

On a weight basis, methimazole is 10 times more potent than the other major antithyroid thionamide used in North America, propylthiouracil,19 and is the active metabolite of the pro-drug carbimazole, which is an antithyroid medication used in the United Kingdom and parts of the former British Commonwealth.14 Traditionally, methimazole has been preferentially used over propylthiouracil due to the risk of fulminant hepatotoxicity carried by the latter,15 with propylthiouracil being preferred in pregnancy due to a perceived lower risk of teratogenic effects. Despite documented teratogenic effects in its published labels,18,19 the true teratogenicity of methimazole appears to be unclear11,15,16 and its place in therapy may change in the future.

Type

Small Molecule

Groups

Approved

Structure

Weight

Average: 114.169
Monoisotopic: 114.025168892

Chemical Formula

C4H6N2S

Synonyms

• 1-Methylimidazole-2(3H)-thione
• Methimazole
• Thiamazol
• Thiamazole
• Thiamazolum
• Tiamazol

External IDs

• NSC 38608
• USAF el-30

Indication

In the United States, methimazole is indicated for the treatment of hyperthyroidism in patients with Graves' disease or toxic multinodular goiter for whom thyroidectomy or radioactive iodine therapy are not appropriate treatment options. Methimazole is also indicated for the amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy.18

In Canada, methimazole carries the above indications and is also indicated for the medical treatment of hyperthyroidism regardless of other available treatment options.19

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Methimazole inhibits the synthesis of thyroid hormones resulting in an alleviation of hyperthyroidism.1819 Onset of action occurs within 12 to 18 hours, and its duration of action is 36 to 72 hours, likely due to concentration of methimazole and some metabolites within the thyroid gland after administration.11

The most serious potential side effect of methimazole therapy is agranulocytosis, and patients should be instructed to monitor for, and report, any signs or symptoms of agranulocytosis such as fever or sore throat. Other cytopenias may also occur during methimazole therapy. There also exists the potential for severe hepatic toxicity with the use of methimazole, and monitoring for signs and symptoms of hepatic dysfunction, such as jaundice, anorexia, pruritus, and elevation in liver transaminases, is prudent in patients using this therapy.18,19

Mechanism of action

Methimazole's primary mechanism of action appears to be interference in an early step in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact method through which methimazole inhibits this step is unclear.6 TPO, along with hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then degrade within thyroid follicular cells to form either thyroxine (T4) or tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland.13

Methimazole may directly inhibit TPO, but has been shown in vivo to instead act as a competitive substrate for TPO, thus becoming iodinated itself and interfering with the iodination of thyroglobulin.6 Another proposed theory is that methimazole’s sulfur moiety may interact directly with the iron atom at the centre of TPO’s heme molecule, thus inhibiting its ability to iodinate tyrosine residues.12 Other proposed mechanisms with weaker evidence include methimazole binding directly to thyroglobulin or direct inhibition of thyroglobulin itself.6

Absorption

Absorption of methimazole after oral administration is rapid and extensive,3,5,1 with an absolute bioavailability of approximately 0.931 and a Tmax ranging from 0.25 to 4.0 hours.3,1 Cmax is slightly, but not significantly, higher in hyperthyroid patients, and both Cmax and AUC are significantly affected by the oral dose administered.3

Volume of distribution

The apparent volume of distribution of methimazole has been reported as roughly 20 L.5 Following oral administration, methimazole is highly concentrated in the thyroid gland - intrathyroidal methimazole levels are approximately 2 to 5 times higher than peak plasma levels, and remain high for 20 hours after ingestion.6

Protein binding

Methimazole exhibits little-to-no protein binding, existing primarily as free drug in the serum.4,5,11

Metabolism

Methimazole is rapidly and extensively metabolized by the liver, mainly via the CYP450 and FMO enzyme systems.7,8 Several metabolites have been identified, though the specific enzyme isoforms responsible for their formation are not entirely clear. One of the first methimazole metabolites identified, 3-methyl-2-thiohydantoin, may contribute to antithyroid activity - its antithyroid activity has been demonstrated in rats and may explain the prolonged duration of iodination inhibition following administration despite methimazole's relatively short half-life.5

A number of metabolites have been investigated as being the culprits behind methimazole-induced hepatotoxicity. Both glyoxal and N-methylthiourea have established cytotoxicity and are known metabolic products of methimazole's dihydrodiol intermediate. Sulfenic and sulfinic acid derivatives of methimazole are thought to be the ultimate toxicants responsible for hepatotoxicity, though their origin is unclear - they may arise from direct oxidation of methimazole via FMO, or from oxidation of N-methylthiourea further downstream in the metabolic process.7,8

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Route of elimination

Urinary excretion of unchanged methimazole has been reported to be between 7% and 12%. Elimination via feces appears to be limited, with a cumulative fecal excretion of 3% after administration of methimazole.3 Enterohepatic circulation also appears to play a role in the elimination of methimazole and its metabolites, as significant amounts of these substances are found in the bile post-administration.11

Half-life

Following a single intravenous bolus injection of 10mg of methimazole, the t1/2 of the distribution phase was 0.17 hours and the t1/2 of the elimination phase was 5.3 hours.1 Methimazole's primary active metabolite, 3-methyl-2-thiohydantoin, has a half-life approximately 3 times longer than its parent drug.5 Renal impairment does not appear to alter the half-life of methimazole, but patients with hepatic impairment showed an increase in half-life roughly proportional to the severity of their impairment - moderate insufficiency resulted in a elimination t1/2 of 7.1 hours, while severe insufficiency resulted in an elimination t1/2 of 22.1 hours.1

There does not appear to be any significant differences in half-life based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).1,2,3

Clearance

Following a single intravenous bolus injection of 10mg of methimazole, clearance was found to be 5.70 L/h.1 Renal impairment does not appear to alter clearance of methimazole, but patients with hepatic impairment showed a reduction in clearance roughly proportional to the severity of their impairment - moderate insufficiency resulted in a clearance of 3.49 L/h, while severe insufficiency resulted in a clearance of 0.83 L/h.1

There does not appear to be any significant differences in clearance based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).1,2,3

Adverse Effects

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Toxicity

The oral LD50 of methimazole in rats is 2250 mg/kg.17 Signs and symptoms of methimazole overdose may include gastrointestinal distress, headache, fever, joint pain, pruritus, and edema. More serious adverse effects, such as aplastic anemia or agranulocytosis, may manifest within hours to days.18,19 Hepatitis, nephrotic syndrome, exfoliative dermatitis, and CNS effects such as neuropathy or CNS depression/stimulation are also potential, albeit less frequent, results of overdose.18,19

Management of overdose involves supportive treatment as dictated by the patient's status.18,19 This may involve monitoring of the patient's vital signs, blood gases, serum electrolytes, or bone marrow function as indicated.19

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Food Interactions

No interactions found.

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Product Images

International/Other Brands

Danantizol (Gador S.A.) / Favistan (Temmler) / Metizol (ICN) / Strumazol (Organon) / Strumazole / Thacapzol (Recip) / Thycapzol (Sandoz) / Thyrozol (Merck) / Tirozol (Merck)

Brand Name Prescription Products

Generic Prescription Products

ATC Codes

H03BB52 — Thiamazole, combinations

• H03BB — Sulfur-containing imidazole derivatives
• H03B — ANTITHYROID PREPARATIONS
• H03 — THYROID THERAPY
• H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS H03BB02 — Thiamazole
• H03BB — Sulfur-containing imidazole derivatives
• H03B — ANTITHYROID PREPARATIONS
• H03 — THYROID THERAPY
• H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

Drug Categories

• Antithyroid agents
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2A6 Inhibitors
• Cytochrome P-450 CYP2A6 Inhibitors (weak)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strong)
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Inhibitors (weak)
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Inhibitors (weak)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strong)
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inhibitors
• Drugs that are Mainly Renally Excreted
• Hormone Antagonists
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Imidazoles
• Immunosuppressive Agents
• Myelosuppressive Agents
• Sulfur Compounds
• Sulfur-Containing Imidazole Derivatives
• Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins
• Thyroid Hormone Synthesis Inhibitor
• Thyroid Hormone Synthesis Inhibitors
• Thyroid Products

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as imidazolethiones. These are aromatic compounds containing an imidazole ring which bears a thioketone group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Azolines

Sub Class

Imidazolines

Direct Parent

Imidazolethiones

Alternative Parents

N-substituted imidazoles / Heteroaromatic compounds / Thioureas / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives

Substituents

Aromatic heteromonocyclic compound / Azacycle / Azole / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Imidazole-2-thione / N-substituted imidazole / Organic nitrogen compound / Organonitrogen compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

imidazoles, thioureas (CHEBI:50673) / a small molecule (CPD-11282)

Affected organisms

• Humans and other mammals

UNII

554Z48XN5E

CAS number

60-56-0

InChI Key

PMRYVIKBURPHAH-UHFFFAOYSA-N

InChI

InChI=1S/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7)

IUPAC Name

1-methyl-2,3-dihydro-1H-imidazole-2-thione

SMILES

CN1C=CNC1=S

Synthesis Reference

李光文李剑平倪国成, "Methimazole synthesizing and purifying method." Chinese Patent CN107162983A, published September, 2017.

General References

1. Jansson R, Lindstrom B, Dahlberg PA: Pharmacokinetic properties and bioavailability of methimazole. Clin Pharmacokinet. 1985 Sep-Oct;10(5):443-50. doi: 10.2165/00003088-198510050-00006. [Article]
2. Cooper DS, Bode HH, Nath B, Saxe V, Maloof F, Ridgway EC: Methimazole pharmacology in man: studies using a newly developed radioimmunoassay for methimazole. J Clin Endocrinol Metab. 1984 Mar;58(3):473-9. doi: 10.1210/jcem-58-3-473. [Article]
3. Okamura Y, Shigemasa C, Tatsuhara T: Pharmacokinetics of methimazole in normal subjects and hyperthyroid patients. Endocrinol Jpn. 1986 Oct;33(5):605-15. doi: 10.1507/endocrj1954.33.605. [Article]
4. Okosieme OE, Lazarus JH: Current trends in antithyroid drug treatment of Graves' disease. Expert Opin Pharmacother. 2016 Oct;17(15):2005-17. doi: 10.1080/14656566.2016.1232388. Epub 2016 Sep 14. [Article]
5. Skellern GG, Knight BI, Low CK, Alexander WD, McLarty DG, Kalk WJ: The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients. Br J Clin Pharmacol. 1980 Feb;9(2):137-43. doi: 10.1111/j.1365-2125.1980.tb05823.x. [Article]
6. Burch HB, Cooper DS: ANNIVERSARY REVIEW: Antithyroid drug therapy: 70 years later Eur J Endocrinol. 2018 Oct 12;179(5):R261-R274. doi: 10.1530/EJE-18-0678. [Article]
7. Heidari R, Niknahad H, Jamshidzadeh A, Eghbal MA, Abdoli N: An overview on the proposed mechanisms of antithyroid drugs-induced liver injury. Adv Pharm Bull. 2015 Mar;5(1):1-11. doi: 10.5681/apb.2015.001. Epub 2015 Mar 5. [Article]
8. Mizutani T, Yoshida K, Murakami M, Shirai M, Kawazoe S: Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: structure-toxicity and metabolic studies. Chem Res Toxicol. 2000 Mar;13(3):170-6. [Article]
9. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]
10. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
11. Clark SM, Saade GR, Snodgrass WR, Hankins GD: Pharmacokinetics and pharmacotherapy of thionamides in pregnancy. Ther Drug Monit. 2006 Aug;28(4):477-83. [Article]
12. Manna D, Roy G, Mugesh G: Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action. Acc Chem Res. 2013 Nov 19;46(11):2706-15. doi: 10.1021/ar4001229. Epub 2013 Jul 24. [Article]
13. Carvalho DP, Dupuy C: Thyroid hormone biosynthesis and release. Mol Cell Endocrinol. 2017 Dec 15;458:6-15. doi: 10.1016/j.mce.2017.01.038. Epub 2017 Jan 31. [Article]
14. Cooper DS: Antithyroid drugs. N Engl J Med. 2005 Mar 3;352(9):905-17. doi: 10.1056/NEJMra042972. [Article]
15. Cooper DS, Laurberg P: Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 2013 Nov;1(3):238-49. doi: 10.1016/S2213-8587(13)70086-X. Epub 2013 Oct 18. [Article]
16. Mallela MK, Strobl M, Poulsen RR, Wendler CC, Booth CJ, Rivkees SA: Evaluation of developmental toxicity of propylthiouracil and methimazole. Birth Defects Res B Dev Reprod Toxicol. 2014 Aug;101(4):300-7. doi: 10.1002/bdrb.21113. Epub 2014 Jun 30. [Article]
17. CaymenChem: Methimazole MSDS [Link]
18. FDA Approved Drug Products: TAPAZOLE (methimazole) oral tablet [Link]
19. DPD Approved Drugs: Methimazole [Link]

External Links

Human Metabolome Database

HMDB0014901

KEGG Drug

D00401

KEGG Compound

C07190

PubChem Compound

1349907

PubChem Substance

46506536

ChemSpider

1131173

BindingDB

50241361

RxNav

6835

ChEBI

50673

ChEMBL

CHEMBL1515

ZINC

ZINC000001187543

Therapeutic Targets Database

DNC001429

PharmGKB

PA450422

PDBe Ligand

MMZ

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Thiamazole

PDB Entries

2gvc / 5ff1 / 5gsn

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View Sample Data

Manufacturers

• Actavis totowa llc
• Caraco pharmaceutical laboratories ltd
• Cedar pharmaceuticals llc
• Mylan pharmaceuticals inc
• Sandoz inc
• King pharmaceuticals inc
• King pharmaceuticals research and development inc sub king pharmaceuticals inc

Packagers

• AAIPharma Inc.
• Actavis Group
• Amerisource Health Services Corp.
• Caraco Pharmaceutical Labs
• Cedar Pharmaceuticals LLC
• Centrix Pharmaceuticals
• Dispensing Solutions
• Eon Labs
• Heartland Repack Services LLC
• Kaiser Foundation Hospital
• King Pharmaceuticals Inc.
• Medisca Inc.
• Mikart Inc.
• Murfreesboro Pharmaceutical Nursing Supply
• Mylan
• Nucare Pharmaceuticals Inc.
• Par Pharmaceuticals
• Philopharm GmbH
• Physicians Total Care Inc.
• Remedy Repack
• Resource Optimization and Innovation LLC
• Southwood Pharmaceuticals
• United Research Laboratories Inc.
• Vangard Labs Inc.

Dosage Forms

Prices

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

Patents

Not Available

State

Solid

Experimental Properties

Predicted Properties

Predicted ADMET Features

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

Mass Spec (NIST)

Download (8.12 KB)

Spectra

Chromatographic Properties

Collision Cross Sections (CCS)

Targets

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Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Substrate

Inhibitor

General Function

Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4)

Specific Function

calcium ion binding

Gene Name

TPO

Uniprot ID

P07202

Uniprot Name

Thyroid peroxidase

Molecular Weight

102961.63 Da

References

1. Sugawara M, Sugawara Y, Wen K: Methimazole and propylthiouracil increase cellular thyroid peroxidase activity and thyroid peroxidase mRNA in cultured porcine thyroid follicles. Thyroid. 1999 May;9(5):513-8. [Article]
2. Manzon RG, Holmes JA, Youson JH: Variable effects of goitrogens in inducing precocious metamorphosis in sea lampreys (Petromyzon marinus). J Exp Zool. 2001 Apr 15;289(5):290-303. [Article]
3. Ferreira AC, de Carvalho Cardoso L, Rosenthal D, de Carvalho DP: Thyroid Ca2+/NADPH-dependent H2O2 generation is partially inhibited by propylthiouracil and methimazole. Eur J Biochem. 2003 Jun;270(11):2363-8. [Article]
4. Magnusson RP, Yu B, Brennan V: Effect of serum thyrotropin levels on the concentration of messenger RNA for thyroid peroxidase in the rat. Acta Endocrinol (Copenh). 1992 May;126(5):460-6. [Article]
5. Chiovato L, Pinchera A: The microsomal/peroxidase antigen: modulation of its expression in thyroid cells. Autoimmunity. 1991;10(4):319-31. [Article]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
7. Burch HB, Cooper DS: ANNIVERSARY REVIEW: Antithyroid drug therapy: 70 years later Eur J Endocrinol. 2018 Oct 12;179(5):R261-R274. doi: 10.1530/EJE-18-0678. [Article]
8. 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]

Enzymes

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Supporting data are limited to in vitro studies.

General Function

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

Specific Function

aromatase activity

Gene Name

CYP1A2

Uniprot ID

P05177

Uniprot Name

Cytochrome P450 1A2

Molecular Weight

58406.915 Da

References

1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [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

1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
2. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). 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 epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)

Specific Function

anandamide 11,12 epoxidase activity

Gene Name

CYP2B6

Uniprot ID

P20813

Uniprot Name

Cytochrome P450 2B6

Molecular Weight

56277.81 Da

References

1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
2. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Current data supporting this enzyme inhibition is limited to one in vitro study.

General Function

A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)

Specific Function

(R)-limonene 6-monooxygenase activity

Gene Name

CYP2C19

Uniprot ID

P33261

Uniprot Name

Cytochrome P450 2C19

Molecular Weight

55944.565 Da

References

1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Data supporting this enzyme action are limited to the findings of 1 in vitro study.

General Function

A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)

Specific Function

(R)-limonene 6-monooxygenase activity

Gene Name

CYP2C9

Uniprot ID

P11712

Uniprot Name

Cytochrome P450 2C9

Molecular Weight

55627.365 Da

References

1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

Specific Function

anandamide 11,12 epoxidase activity

Gene Name

CYP2D6

Uniprot ID

P10635

Uniprot Name

Cytochrome P450 2D6

Molecular Weight

55768.94 Da

References

1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [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

1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
2. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

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

1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Substrate

General Function

Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds (PubMed:10759686, PubMed:30381441, PubMed:32156684). Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite (PubMed:9776311). TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly impacts both platelet responsiveness and rate of thrombus formation (PubMed:29981269)

Specific Function

albendazole monooxygenase activity

Gene Name

FMO3

Uniprot ID

P31513

Uniprot Name

Flavin-containing monooxygenase 3

Molecular Weight

60032.975 Da

References

1. Heidari R, Niknahad H, Jamshidzadeh A, Eghbal MA, Abdoli N: An overview on the proposed mechanisms of antithyroid drugs-induced liver injury. Adv Pharm Bull. 2015 Mar;5(1):1-11. doi: 10.5681/apb.2015.001. Epub 2015 Mar 5. [Article]

Drug created at June 13, 2005 13:24 / Updated at November 11, 2024 10:58