CYP1A2

Cytochrome P450, family 1, subfamily A, polypeptide 2
PDB rendering based on 2hi4.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2HI4​
Identifiers
Symbols	CYP1A2 ; CP12; P3-450; P450(PA)
External IDs	OMIM: 124060 MGI: 88589 HomoloGene: 68082 ChEMBL: 3356 GeneCards: CYP1A2 Gene
EC number	1.14.14.1
Gene ontology Molecular function • monooxygenase activity • iron ion binding • electron carrier activity • oxidoreductase 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 • enzyme binding • heme binding • demethylase activity • caffeine oxidase activity • aromatase activity Cellular component • endoplasmic reticulum membrane • intracellular membrane-bounded organelle Biological process • steroid catabolic process • porphyrin-containing compound metabolic process • xenobiotic metabolic process • toxin biosynthetic process • post-embryonic development • alkaloid metabolic process • regulation of gene expression • monoterpenoid metabolic process • drug metabolic process • dibenzo-p-dioxin metabolic process • arachidonic acid metabolic process • epoxygenase P450 pathway • lung development • methylation • response to estradiol • response to lipopolysaccharide • monocarboxylic acid metabolic process • response to immobilization stress • drug catabolic process • exogenous drug catabolic process • small molecule metabolic process • cellular respiration • heterocycle metabolic process • hydrogen peroxide biosynthetic process • oxidation-reduction process • oxidative demethylation • cellular response to cadmium ion • oxidative deethylation • omega-hydroxylase P450 pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
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

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.^[1] In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.^[2]

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 acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region.^[3]

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).^[4] 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.^[5][6][7][8] 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][10][11] 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.

Effect of diet

Expression of CYP1A2 appears to be induced by various dietary constituents.^[13] 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.^[14]

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, or more than 80% decrease in clearance.^[15]
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[15]
• Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.^[15]

Substrates	Inhibitors	Inducers
many antidepressants amitriptyline[15][16] (tricyclic antidepressant) clomipramine[15][16] (tricyclic antidepressant) imipramine[15][16] (tricyclic antidepressant) agomelatine some atypical antipsychotics clozapine[15][16] olanzapine[15][16] haloperidol[15][16] (typical antipsychotic) caffeine[15][16] (xanthine, stimulant) ropivacaine[15][16] (local anaesthetic) theophylline[15][16] (xanthine, in respiratory diseases) zolmitriptan[15][16] (serotonin receptor agonist) melatonin[16] (antioxidant, sleep-inducer) tamoxifen[16] (SERM) erlotinib[17] (Tarceva, a tyrosine kinase inhibitor) cyclobenzaprine[15] (muscle relaxant, depressant) estradiol[15] (in hypoestrogenism) fluvoxamine[15] (SSRI antidepressant) mexiletine[15] (antiarrhythmic agent) naproxen[15] (NSAID) ondansetron[15] (5-HT3 antagonist) phenacetin[15] (analgesic) paracetamol[15] (analgesic, antipyretic) propranolol[15] (beta blocker) riluzole[15] (in amyotrophic lateral sclerosis) tacrine[15] (parasympathomimetic) tizanidine[15] (α-2 adrenergic agonist) verapamil[15] (calcium channel blocker) warfarin[15] (anticoagulant) zileuton[15] (in asthma)	Strong: ciprofloxacin[15][16] (fluoroquinolone bactericidal) Many other fluoroquinolones (broad-spectrum antibiotics) fluvoxamine[15][16] (SSRI antidepressant) verapamil[16] (calcium channel blocker) Moderate St. John's wort[18] Herbs and herbal Teas Peppermint, German Chamomile(Chamazulene), and Dandelion Teas[19] Weak cimetidine[15] (H2-receptor antagonist) caffeine[20] Unspecified potency: amiodarone[15] (antiarrhythmic agent) interferon[15] (antiviral, antiseptic, antioncogenic) methoxsalen[15] (in psoriasis) Mibefradil[15] (calcium channel blocker) Some foods grapefruit juice (its bitter flavanone naringenin)[21] cumin[14] turmeric[14] isoniazid[22]	tobacco[15][16] Some foods/herbs broccoli[14][15] brussels sprouts[15] Echinacea[23] chargrilled meat[15] cauliflower[14] insulin[15] (in diabetes) Methylcholanthrene[15] (carcinogen) modafinil[15] (eugeroic) nafcillin[15] (beta-lactam antibiotic) beta-Naphthoflavone[15] (chemopreventive) omeprazole[15] (proton pump inhibitor)

See also

• Cytochrome P450 oxidase

References

1. 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.
2. 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.
3. "Entrez Gene: cytochrome P450".
4. 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.
5. 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.
6. 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. PMID 24345640.
7. He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. doi:10.1111/1753-0407.12358. PMID 26621325.
8. 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. PMID 25240260.
9. 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. PMID 24634501.
10. 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.
11. 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. PMID 25240260.
12. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:2-12. doi: 10.1016/j.prostaglandins.2014.09.001. Epub 2014 Sep 18. Review
13. 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.
14. Sanday, Kate (17 October 2011), "South Asians and Europeans react differently to common drugs", University of Sydney Faculty of Pharmacy News
15. Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011
16. Swedish environmental classification of pharmaceuticals - FASS (drug catalog) - Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
17. "Erlotinib". Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1
18. 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.
19. Maliakal, Pius. "Effect of herbal teas on hepatic drug metabolizing enzymes in rats". Journal of Pharmacy and Pharmacology. Retrieved 29 December 2012.
20. "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". U.S. Food and Drug Administration.
21. 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:10.1016/0024-3205(96)00417-1. PMC 1381556. PMID 8485024.
22. Wen X, Wang JS, Neuvonen PJ, Backman JT. "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes.". PMID 11868802.
23. 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.

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; The Fate of Foreign Compounds in Biological Systems 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. 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. 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.
• 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.