Cytochrome P450 1A2 (abbreviatedCYP1A2), a member of thecytochrome P450 mixed-function oxidase system, is involved in the metabolism ofxenobiotics in the human body.[5] In humans, the CYP1A2 enzyme is encoded by theCYP1A2gene.[6]
CYP1A2 is a member of thecytochrome P450 superfamily of enzymes. The cytochrome P450 proteins aremonooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP1A2 localizes to theendoplasmic reticulum and its expression is induced by somepolycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme includecaffeine, aflatoxin B1, andparacetamol (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region.[7]
CYP1A2 also metabolizespolyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. It has monoxygenase activity for certain of these fatty acids in that it metabolizesarachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see20-Hydroxyeicosatetraenoic acid) but also hasepoxygenase activity in that it metabolizesdocosahexaenoic acid toepoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizeseicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ).[8]
19-HETE is an inhibitor of20-HETE, a broadly active signaling molecule, e.g., it constrictsarterioles, elevates blood pressure, promotesinflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated. The EDP (epoxydocosapentaenoic acid) and EEQ (epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibitangiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.[9][10][11][12] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of theomega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.[9][12][13] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation byepoxide hydrolases, particularlysoluble epoxide hydrolase, and therefore act locally.
CYP1A2 is not regarded as being a major contributor to forming the aforementioned epoxides[12] but could act locally in certain tissues to do so.
The authoritative list of starallele nomenclature for CYP1A2 along with activity scores is kept by PharmVar.[14]
Expression of CYP1A2 appears to be induced by various dietary constituents.[15] Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such ascumin andturmeric, ingredients known to inhibit the enzyme.[16]
A single 2006 paper found CYP1A2 to be involved in the metabolization ofcaffeine, and the presence of alleles that make this metabolization slow have been associated with an increased risk of nonfatalmyocardial infarction for those who drink a lot ofcoffee (4 or more cups per day).[17]
Inhibitors of CYP1A2 can be classified by theirpotency, such as:
Strong inhibitor being one that causes at least a 5-fold increase in the plasmaAUC values of sensitive substrates metabolized through CYP1A2, or more than 80% decrease inclearance thereof.[18]
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP1A2, or 50-80% decrease in clearance thereof.[18]
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP1A2, or 20-50% decrease in clearance thereof.[18]
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^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW (January 2004). "Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants".Pharmacogenetics.14 (1):1–18.doi:10.1097/00008571-200401000-00001.PMID15128046.S2CID18448751.
^Jaiswal AK, Nebert DW, McBride OW, Gonzalez FJ (1987). "Human P(3)450: cDNA and complete protein sequence, repetitive Alu sequences in the 3' nontranslated region, and localization of gene to chromosome 15".Journal of Experimental Pathology.3 (1):1–17.PMID3681487.
^Alkattan A, Alsalameen E (June 2021). "Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment".Expert Opinion on Drug Metabolism & Toxicology.17 (6):685–695.doi:10.1080/17425255.2021.1925249.PMID33931001.S2CID233470717.
^Savage RA, Zafar N, Yohannan S, Miller JM (2021). "article-35398".Melatonin. Treasure Island (FL): StatPearls Publishing.PMID30521244.Archived from the original on 21 June 2021. Retrieved15 November 2021.Ninety percent of melatonin is metabolized in the liver primarily by the enzyme CYP1A2
^"Erlotinib".Archived from the original on 24 December 2019. Retrieved10 April 2018.Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1
^ab"Verapamil: Drug information. Lexicomp".UpToDate.Archived from the original on 13 January 2019. Retrieved13 January 2019.Metabolism/Transport Effects: Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP3A4 (moderate), P-glycoprotein/ABCB1
^Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD (January 2004). "The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo".Clinical Pharmacology and Therapeutics.75 (1):89–100.doi:10.1016/j.clpt.2003.09.013.PMID14749695.S2CID8375888.
^Wen X, Wang JS, Neuvonen PJ, Backman JT (January 2002). "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes".European Journal of Clinical Pharmacology.57 (11):799–804.doi:10.1007/s00228-001-0396-3.PMID11868802.S2CID19299097.
^Zhao Y, Hellum BH, Liang A, Nilsen OG (June 2015). "Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs".Phytotherapy Research.29 (6):825–834.doi:10.1002/ptr.5285.PMID25640685.S2CID24002845.
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This article incorporatespublic domain material from"PharmVar".Reference Sequence collection.National Center for Biotechnology Information. Retrieved20 May 2020.
