CYP1A2

Cytochrome P450, family 1, subfamily A, polypeptide 2
PDB rendering based on 2hi4.
Available structures PDB 2hi4
Identifiers
Symbols	CYP1A2; CP12; P3-450; P450(PA)
External IDs	OMIM: 124060 MGI: 88589 HomoloGene: 68082 GeneCards: CYP1A2 Gene
EC number	1.14.14.1
Gene Ontology Molecular function • monooxygenase activity • 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 • oxygen binding • oxygen binding • enzyme binding • heme binding • demethylase activity • caffeine oxidase activity • metal ion binding • aromatase activity Cellular component • endoplasmic reticulum • endoplasmic reticulum membrane • endoplasmic reticulum membrane • microsome • membrane Biological process • steroid catabolic process • cellular aromatic compound metabolic process • porphyrin 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 • lung development • methylation • monocarboxylic acid metabolic process • drug catabolic process • exogenous drug catabolic process • cellular respiration • heterocycle metabolic process • hydrogen peroxide biosynthetic process • oxidation-reduction process • oxidative demethylation • oxidative deethylation 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_000761.3	NM_009993.3
RefSeq (protein)	NP_000752.2	NP_034123.1
Location (UCSC)	Chr 15: 75.04 – 75.05 Mb	Chr 9: 57.52 – 57.53 Mb
PubMed search	[1]	[2]

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]

Expression of CYP1A2 appears to be induced by various dietary constituents.^[3]Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2,lower levels of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as cumin and tumeric, ingredients known to inhibit the enzyme.^[4]

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.^[5]

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.^[6]
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[6]
• 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.^[6]

Substrates	Inhibitors	Inducers
many antidepressants amitriptyline[6][7] (tricyclic antidepressant) clomipramine[6][7] (tricyclic antidepressant) imipramine[6][7] (tricyclic antidepressant) agomelatine some atypical antipsychotics clozapine[6][7] olanzapine[6][7] haloperidol[6][7] (typical antipsychotic) caffeine[6][7] (stimulant) ropivacaine[6][7] (local anaesthetic) theophylline[6][7] (xanthine, in respiratory diseases) zolmitriptan[6][7] (serotonin receptor agonist) melatonin[7] (antioxidant, sleep-inducer) tamoxifen[7] (SERM) erlotinib[8] (Tarceva, a tyrosine kinase inhibitor) cyclobenzaprine[6] (muscle relaxant, depressant) estradiol[6] (in hypoestrogenism) fluvoxamine[6] (SSRI antidepressant) mexiletine[6] (antiarrhythmic agent) naproxen[6] (NSAID) ondansetron[6] (5-HT3 antagonist) phenacetin[6] (analgesic) paracetamol[6] (analgesic, antipyretic) propranolol[6] (beta blocker) riluzole[6] (in amyotrophic lateral sclerosis) tacrine[6] (parasympathomimetic) tizanidine[6] (α-2 adrenergic agonist) verapamil[6] (calcium channel blocker) warfarin[6] (anticoagulant) zileuton[6] (in asthma)	Strong: ciprofloxacin[6][7] (fluoroquinolone bactericidal) Many other fluoroquinolones (broad-spectrum antibiotics) fluvoxamine[7][6] (SSRI antidepressant) verapamil[7] (calcium channel blocker) Weak cimetidine[6] (H2-receptor antagonist) Unspecified potency: grapefruit juice (its bitter flavanone naringenin)[9] amiodarone[6] (antiarrhythmic agent) interferon[6] (antiviral, antiseptic, antioncogenic) methoxsalen[6] (in psoriasis) Mibefradil[6] (calcium channel blocker)	tobacco[7][6] Some foods broccoli[6] brussels sprouts[6] chargrilled meat[6] insulin[6] (in diabetes) Methylcholanthrene[6] (carcinogen) modafinil[6] (eugeroic) nafcillin[6] (beta-lactam antibiotic) beta-Naphthoflavone[6] (chemopreventive) omeprazole[6] (proton pump inhibitor)

References

1. ^ 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. 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". J. Exp. Pathol. 3 (1): 1–17. PMID 3681487. 
3. ^ Fontana R, Lown K, Paine M, Fortlage L, Santella R, Felton J, Knize M, Greenberg A, Watkins P (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. 
4. ^ http://sydney.edu.au/news/pharm/1311.html?newsstoryid=7969
5. ^ "Entrez Gene: cytochrome P450". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1544. 
6. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as} Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on July 2011
7. ^ ^{a b c d e f g h i j k l m n o p} Swedish environmental classification of pharmaceuticals - FASS (drug catalog) - Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
8. ^ "Erlotinib". http://www.drugs.com/ppa/erlotinib.html. "Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1" 
9. ^ Edwards DJ, Bernier SM (1996). "Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man". Life Sciences 59 (13): 1025–1030. doi:10.1016/0024-3205(96)00417-1. PMC 1381556. PMID 8485024. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1381556. 

Further reading

• Meijerman I, Beijnen J, Schellens J (2006). "Herb-drug interactions in oncology: focus on mechanisms of induction". Oncologist 11 (7): 742–52. doi:10.1634/theoncologist.11-7-742. PMID 16880233. 
• Smith G, Stubbins MJ, Harries LW, Wolf CR (1999). "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 Sci. Publ. (148): 173–95. PMID 10493258. 
• Ikeya K, Jaiswal AK, Owens RA, et al. (1990). "Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression.". Mol. Endocrinol. 3 (9): 1399–408. doi:10.1210/mend-3-9-1399. PMID 2575218. 
• Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (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.". Proc. Natl. Acad. Sci. U.S.A. 86 (20): 7696–700. doi:10.1073/pnas.86.20.7696. PMC 298137. PMID 2813353. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298137. 
• Quattrochi LC, Okino ST, Pendurthi UR, Tukey RH (1986). "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, et al. (1986). "Human cytochrome P-450 4 mRNA and gene: part of a multigene family that contains Alu sequences in its mRNA.". Proc. Natl. Acad. Sci. U.S.A. 83 (18): 6731–5. doi:10.1073/pnas.83.18.6731. PMC 386583. PMID 3462722. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=386583. 
• Wrighton SA, Campanile C, Thomas PE, et al. (1986). "Identification of a human liver cytochrome P-450 homologous to the major isosafrole-inducible cytochrome P-450 in the rat.". Mol. Pharmacol. 29 (4): 405–10. PMID 3517618. 
• Jaiswal AK, Nebert DW, Gonzalez FJ (1986). "Human P3(450): cDNA and complete amino acid sequence.". Nucleic Acids Res. 14 (16): 6773–4. doi:10.1093/nar/14.16.6773. PMC 311685. PMID 3755823. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=311685. 
• 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 Metab. Dispos. 21 (1): 43–9. PMID 8095225. 
• Schweikl H, Taylor JA, Kitareewan S, et al. (1994). "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, et al. (1996). "7-Ethoxycoumarin O-deethylation catalyzed by cytochromes P450 1A2 and 2E1 in human liver microsomes.". Biochem. Pharmacol. 51 (3): 313–9. doi:10.1016/0006-2952(95)02178-7. PMID 8573198. 
• Hakkola J, Raunio H, Purkunen R, et al. (1996). "Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy.". Biochem. Pharmacol. 52 (2): 379–83. doi:10.1016/0006-2952(96)00216-X. PMID 8694864. 
• Guengerich FP, Johnson WW (1998). "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, et al. (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, et al. (1998). "Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues.". Eur. J. Cancer 34 (6): 914–20. doi:10.1016/S0959-8049(98)00034-3. PMID 9797707. 
• Huang JD, Guo WC, Lai MD, et al. (1999). "Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese.". Drug Metab. Dispos. 27 (1): 98–101. PMID 9884316. 
• Tatemichi M, Nomura S, Ogura T, et al. (1999). "Mutagenic activation of environmental carcinogens by microsomes of gastric mucosa with intestinal metaplasia.". Cancer Res. 59 (16): 3893–8. PMID 10463577. 

See also

• Cytochrome P450 oxidase

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