CYP1A2

Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body.[5] In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.[6]

CYP1A2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2HI4
Identifiers
Aliases	CYP1A2, CP12, P3-450, P450(PA), cytochrome P450 family 1 subfamily A member 2, Cytochrome P450 1A2, CYPIA2
External IDs	OMIM: 124060 MGI: 88589 HomoloGene: 68082 GeneCards: CYP1A2
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q24.1 Start 74,748,845 bp[1] End 74,756,607 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 B|9 31.3 cM Start 57,676,937 bp[2] End 57,683,703 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • iron ion binding • demethylase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • metal ion binding • caffeine oxidase activity • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • enzyme binding • oxidoreductase activity • aromatase activity • electron transfer activity • monooxygenase activity Cellular component • organelle membrane • endoplasmic reticulum membrane • intracellular membrane-bounded organelle • membrane • endoplasmic reticulum Biological process • response to immobilization stress • toxin metabolic process • steroid metabolic process • response to estradiol • alkaloid metabolic process • response to organic cyclic compound • lung development • lipid metabolism • exogenous drug catabolic process • epoxygenase P450 pathway • cellular response to cadmium ion • post-embryonic development • monocarboxylic acid metabolic process • response to organic substance • oxidative deethylation • oxidative demethylation • drug catabolic process • response to lipopolysaccharide • methylation • steroid catabolic process • omega-hydroxylase P450 pathway • dibenzo-p-dioxin metabolic process • heterocycle metabolic process • cellular respiration • cellular aromatic compound metabolic process • regulation of gene expression • hydrogen peroxide biosynthetic process • monoterpenoid metabolic process • drug metabolic process • xenobiotic metabolic process • oxidation-reduction process • response to drug • porphyrin-containing compound metabolic process • toxin biosynthetic process • cellular response to copper ion • electron transport chain • long-chain fatty acid biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1544	13077
Ensembl	ENSG00000140505	ENSMUSG00000032310
UniProt	P05177	P00186
RefSeq (mRNA)	NM_000761	NM_009993
RefSeq (protein)	NP_000752	NP_034123
Location (UCSC)	Chr 15: 74.75 – 74.76 Mb	Chr 9: 57.68 – 57.68 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

CYP1A2 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP1A2 localizes to the endoplasmic reticulum and its expression is induced by some polycyclic 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 include caffeine, aflatoxin B1, and paracetamol (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region.[7]

CYP1A2 also metabolizes polyunsaturated 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 metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).[8]

19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation 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 (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see 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; inhibit angiogenesis, 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 the omega-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 by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally.

CYP1A2 is not regarded as being a major contributor to forming the cited epoxides[12] but could act locally in certain tissues to do so.

The authoratitive list of star allele nomenclature for CYP1A2 along with activity scores is kept by PharmVar[14]

Effect of diet

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 as cumin and turmeric, ingredients known to inhibit the enzyme.[16]

Ligands

Following is a table of selected substrates, inducers and inhibitors of CYP1A2.

Inhibitors of CYP1A2 can be classified by their potency, such as:

• Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP1A2, or more than 80% decrease in clearance thereof.[17]
• 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.[17]
• 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.[17]

Substrates	Inhibitors	Inducers
dietary flavonoids naringenin[18] naringin[18] quercetin[18] rutin[18] alosetron [19] (5-HT3 antagonist) many antidepressants amitriptyline[20][21] (tricyclic antidepressant) clomipramine[20][21] (tricyclic antidepressant) imipramine[20][21] (tricyclic antidepressant) agomelatine duloxetine[20] (SNRI, sensitive substrates of CYP1A2[20]) some atypical antipsychotics clozapine[20][21] olanzapine[20][21] haloperidol[20][21] (typical antipsychotic) caffeine[20][21] (xanthine, stimulant) ropivacaine[20][21] (local anaesthetic) theophylline[20][21] (xanthine, in respiratory diseases) zolmitriptan[20][21] (serotonin receptor agonist) melatonin[21] (antioxidant, sleep-inducer) tamoxifen[21] (SERM) erlotinib[22] (Tarceva, a tyrosine kinase inhibitor) cyclobenzaprine[20] (muscle relaxant, depressant) estradiol[20] (in hypoestrogenism) fluvoxamine[20] (SSRI antidepressant) mexiletine[20] (antiarrhythmic agent) naproxen[20] (NSAID) ondansetron[20] (5-HT3 antagonist) phenacetin[20] (analgesic) paracetamol[20] (analgesic, antipyretic) propranolol[20] (beta blocker) ramelteon[19] riluzole[20] (in amyotrophic lateral sclerosis) tacrine[20] (parasympathomimetic) tasimelteon [19] tizanidine[20] (α-2 adrenergic agonist) verapamil[20] ( of calcium channel blocker, also classified as moderate sensitive substrate in CYP1A2[23]) warfarin[20] (anticoagulant) zileuton[20] (in asthma)	Strong: Many fluoroquinolones (broad-spectrum antibiotics), including: enoxacin[19] ciprofloxacin[20][21][19] fluvoxamine[20][21] (SSRI antidepressant) Moderate St. John's wort[24] methoxsalen[19] (in psoriasis) mexiletine[19] oral contraceptives[19] Weak acyclovir[19] allopurinol[19] mexiletine[19] cimetidine[20] (H2-receptor antagonist) caffeine[25] echinacea[26] peginterferon alpha-2a[19] theophylline[27] piperine[19] verapamil (a non-dihydropyridine calcium channel blocker) according to UpToDate.[23] However, FASS, a Swedish national authority, attributes verapamil to strong CYP1A2 inhibitor.[21] zileuton[19] Unspecified potency: interferon[20] (antiviral, antiseptic, antioncogenic) Mibefradil[20] (calcium channel blocker) Some foods grapefruit juice (its bitter flavanone naringenin)[28] cumin[16] turmeric[16] isoniazid[29]	Moderate inducers:[19] tobacco[20][21][19] phenytoin[19] rifampin[19] ritonavir[19] teriflunomide[19] Unspecified potency: Some foods/herbs: liquorice[27] brassica[27] broccoli[16][20] brussels sprouts[20] cauliflower[16] chargrilled meat[20] insulin[20] (in diabetes) methylcholanthrene[20] (carcinogen) modafinil[20] (eugeroic) nafcillin[20] (beta-lactam antibiotic) beta-Naphthoflavone[20] (chemopreventive) Some proton pump inhibitors: omeprazole[20][19] lansoprazole[19]

See also

• Cytochrome P450 oxidase

References

1. GRCh38: Ensembl release 89: ENSG00000140505 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032310 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW (Jan 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. PMID 15128046. S2CID 18448751.
6. 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. PMID 3681487.
7. "Entrez Gene: cytochrome P450".
8. Westphal C, Konkel A, Schunck WH (Nov 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326.
9. Fleming I (Oct 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID 25244930.
10. Zhang G, Kodani S, Hammock BD (Jan 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
11. He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. 8 (3): 305–13. doi:10.1111/1753-0407.12358. PMID 26621325.
12. Wagner K, Vito S, Inceoglu B, Hammock BD (Oct 2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators. 113-115: 2–12. doi:10.1016/j.prostaglandins.2014.09.001. PMC 4254344. PMID 25240260.
13. Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH (Mar 2014). "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research. 55 (6): 1150–1164. doi:10.1194/jlr.M047357. PMC 4031946. PMID 24634501.
14. "PharmVar". PharmVar. Retrieved 20 May 2020.
15. Fontana RJ, Lown KS, Paine MF, Fortlage L, Santella RM, Felton JS, Knize MG, Greenberg A, Watkins PB (Jul 1999). "Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers". Gastroenterology. 117 (1): 89–98. doi:10.1016/S0016-5085(99)70554-8. PMID 10381914.
16. Sanday, Kate (17 October 2011), "South Asians and Europeans react differently to common drugs", University of Sydney Faculty of Pharmacy News
17. Center for Drug Evaluation and Research. "Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". www.fda.gov. Retrieved 2016-06-01.
18. "In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9".
19. "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers".
20. Flockhart DA (2007). "Drug Interactions Flockhart Table". Indiana University School of Medicine.
21. Swedish environmental classification of pharmaceuticals - FASS (drug catalog) - Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
22. "Erlotinib". Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1
23. "Verapamil: Drug information. Lexicomp". UpToDate. Retrieved 2019-01-13. 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
24. Dostalek M, Pistovcakova J, Jurica J, Sulcová A, Tomandl J (Sep 2011). "The effect of St John's wort (hypericum perforatum) on cytochrome p450 1a2 activity in perfused rat liver". Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia. 155 (3): 253–7. doi:10.5507/bp.2011.047. PMID 22286810.
25. "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". U.S. Food and Drug Administration. 2019-02-09.
26. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD (Jan 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. PMID 14749695.
27. Briguglio, M.; Hrelia, S.; Malaguti, M.; Serpe, L.; Canaparo, R.; Dell'Osso, B.; Galentino, R.; De Michele, S.; Dina, C. Z.; Porta, M.; Banfi, G. (2018). "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics. 10 (4): 277. doi:10.3390/pharmaceutics10040277. PMC 6321138. PMID 30558213.
28. Fuhr U, Klittich K, Staib AH (Apr 1993). "Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man". British Journal of Clinical Pharmacology. 35 (4): 431–6. doi:10.1111/j.1365-2125.1993.tb04162.x. PMC 1381556. PMID 8485024.
29. Wen X, Wang JS, Neuvonen PJ, Backman JT (Jan 2002). "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes". Eur J Clin Pharmacol. 57 (11): 799–804. doi:10.1007/s00228-001-0396-3. PMID 11868802. S2CID 19299097.

External links

• Human CYP1A2 genome location and CYP1A2 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P05177 (Cytochrome P450 1A2) at the PDBe-KB.

Further reading

• Meijerman I, Beijnen JH, Schellens JH (2006). "Herb-drug interactions in oncology: focus on mechanisms of induction". The Oncologist. 11 (7): 742–52. doi:10.1634/theoncologist.11-7-742. PMID 16880233.
• Smith G, Stubbins MJ, Harries LW, Wolf CR (Dec 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
• Landi MT, Sinha R, Lang NP, Kadlubar FF (1999). "Human cytochrome P4501A2". IARC Scientific Publications (148): 173–95. PMID 10493258.
• Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S (Sep 1989). "Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression". Molecular Endocrinology. 3 (9): 1399–408. doi:10.1210/mend-3-9-1399. PMID 2575218.
• Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (Oct 1989). "Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines". Proceedings of the National Academy of Sciences of the United States of America. 86 (20): 7696–700. Bibcode:1989PNAS...86.7696B. doi:10.1073/pnas.86.20.7696. PMC 298137. PMID 2813353.
• Quattrochi LC, Okino ST, Pendurthi UR, Tukey RH (Oct 1985). "Cloning and isolation of human cytochrome P-450 cDNAs homologous to dioxin-inducible rabbit mRNAs encoding P-450 4 and P-450 6". DNA. 4 (5): 395–400. doi:10.1089/dna.1985.4.395. PMID 3000715.
• Quattrochi LC, Pendurthi UR, Okino ST, Potenza C, Tukey RH (Sep 1986). "Human cytochrome P-450 4 mRNA and gene: part of a multigene family that contains Alu sequences in its mRNA". Proceedings of the National Academy of Sciences of the United States of America. 83 (18): 6731–5. Bibcode:1986PNAS...83.6731Q. doi:10.1073/pnas.83.18.6731. PMC 386583. PMID 3462722.
• Wrighton SA, Campanile C, Thomas PE, Maines SL, Watkins PB, Parker G, Mendez-Picon G, Haniu M, Shively JE, Levin W (Apr 1986). "Identification of a human liver cytochrome P-450 homologous to the major isosafrole-inducible cytochrome P-450 in the rat". Molecular Pharmacology. 29 (4): 405–10. PMID 3517618.
• Jaiswal AK, Nebert DW, Gonzalez FJ (Aug 1986). "Human P3(450): cDNA and complete amino acid sequence". Nucleic Acids Research. 14 (16): 6773–4. doi:10.1093/nar/14.16.6773. PMC 311685. PMID 3755823.
• Eugster HP, Probst M, Würgler FE, Sengstag C (1993). "Caffeine, estradiol, and progesterone interact with human CYP1A1 and CYP1A2. Evidence from cDNA-directed expression in Saccharomyces cerevisiae". Drug Metabolism and Disposition. 21 (1): 43–9. PMID 8095225.
• Schweikl H, Taylor JA, Kitareewan S, Linko P, Nagorney D, Goldstein JA (Oct 1993). "Expression of CYP1A1 and CYP1A2 genes in human liver". Pharmacogenetics. 3 (5): 239–49. doi:10.1097/00008571-199310000-00003. PMID 8287062.
• Yamazaki H, Inoue K, Mimura M, Oda Y, Guengerich FP, Shimada T (Feb 1996). "7-Ethoxycoumarin O-deethylation catalyzed by cytochromes P450 1A2 and 2E1 in human liver microsomes". Biochemical Pharmacology. 51 (3): 313–9. doi:10.1016/0006-2952(95)02178-7. PMID 8573198.
• Hakkola J, Raunio H, Purkunen R, Pelkonen O, Saarikoski S, Cresteil T, Pasanen M (Jul 1996). "Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy". Biochemical Pharmacology. 52 (2): 379–83. doi:10.1016/0006-2952(96)00216-X. PMID 8694864.
• Guengerich FP, Johnson WW (Dec 1997). "Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase: rapid reduction in the absence of substrate and variations among cytochrome P450 systems". Biochemistry. 36 (48): 14741–50. doi:10.1021/bi9719399. PMID 9398194.
• Wacke R, Kirchner A, Prall F, Nizze H, Schmidt W, Fischer U, Nitschke FP, Adam U, Fritz P, Belloc C, Drewelow B (May 1998). "Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis". Pancreas. 16 (4): 521–8. doi:10.1097/00006676-199805000-00011. PMID 9598815. S2CID 24670684.
• Macé K, Bowman ED, Vautravers P, Shields PG, Harris CC, Pfeifer AM (May 1998). "Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues". European Journal of Cancer. 34 (6): 914–20. doi:10.1016/S0959-8049(98)00034-3. PMID 9797707.
• Huang JD, Guo WC, Lai MD, Guo YL, Lambert GH (Jan 1999). "Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese". Drug Metabolism and Disposition. 27 (1): 98–101. PMID 9884316.
• Tatemichi M, Nomura S, Ogura T, Sone H, Nagata H, Esumi H (Aug 1999). "Mutagenic activation of environmental carcinogens by microsomes of gastric mucosa with intestinal metaplasia". Cancer Research. 59 (16): 3893–8. PMID 10463577.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.