CYP1A2 explained

Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human 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 paracetamol (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-eicosatetraenoic acid and 17S,18R-eicosatetraenoic 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. 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; 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] 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 aforementioned epoxides but could act locally in certain tissues to do so.

The authoritative list of star allele nomenclature for CYP1A2 along with activity scores is kept by PharmVar.

Effect of diet

Expression of CYP1A2 appears to be induced by various dietary constituents.^[10] 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.

Possible association with caffeine metabolisation

A single 2006 paper found CYP1A2 to be involved in the metabolization of caffeine, and the presence of alleles that make this metabolization slow have been associated with an increased risk of nonfatal myocardial infarction for those who drink a lot of coffee (4 or more cups per day).^[11]

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.^[12]
• 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.
• 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.

See also

• Drug metabolism

Further reading

• Meijerman I, Beijnen JH, Schellens JH . Herb-drug interactions in oncology: focus on mechanisms of induction . The Oncologist . 11 . 7 . 742–752 . 2006 . 16880233 . 10.1634/theoncologist.11-7-742 .
• Smith G, Stubbins MJ, Harries LW, Wolf CR . Molecular genetics of the human cytochrome P450 monooxygenase superfamily . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 28 . 12 . 1129–1165 . December 1998 . 9890157 . 10.1080/004982598238868 .
• Landi MT, Sinha R, Lang NP, Kadlubar FF . Human cytochrome P4501A2 . IARC Scientific Publications . 148 . 173–195 . 1999 . 10493258 .
• Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S . Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression . Molecular Endocrinology . 3 . 9 . 1399–1408 . September 1989 . 2575218 . 10.1210/mend-3-9-1399 . free .
• Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF . 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 . 7696–7700 . October 1989 . 2813353 . 298137 . 10.1073/pnas.86.20.7696 . free . 1989PNAS...86.7696B .
• Quattrochi LC, Okino ST, Pendurthi UR, Tukey RH . 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 . October 1985 . 3000715 . 10.1089/dna.1985.4.395 .
• Quattrochi LC, Pendurthi UR, Okino ST, Potenza C, Tukey RH . 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 . 6731–6735 . September 1986 . 3462722 . 386583 . 10.1073/pnas.83.18.6731 . free . 1986PNAS...83.6731Q .
• Wrighton SA, Campanile C, Thomas PE, Maines SL, Watkins PB, Parker G, Mendez-Picon G, Haniu M, Shively JE, Levin W . Identification of a human liver cytochrome P-450 homologous to the major isosafrole-inducible cytochrome P-450 in the rat . Molecular Pharmacology . 29 . 4 . 405–410 . April 1986 . 3517618 .
• Jaiswal AK, Nebert DW, Gonzalez FJ . Human P3(450): cDNA and complete amino acid sequence . Nucleic Acids Research . 14 . 16 . 6773–6774 . August 1986 . 3755823 . 311685 . 10.1093/nar/14.16.6773 .
• Eugster HP, Probst M, Würgler FE, Sengstag C . Caffeine, estradiol, and progesterone interact with human CYP1A1 and CYP1A2. Evidence from cDNA-directed expression in Saccharomyces cerevisiae . Drug Metabolism and Disposition . 21 . 1 . 43–49 . 1993 . 8095225 .
• Schweikl H, Taylor JA, Kitareewan S, Linko P, Nagorney D, Goldstein JA . Expression of CYP1A1 and CYP1A2 genes in human liver . Pharmacogenetics . 3 . 5 . 239–249 . October 1993 . 8287062 . 10.1097/00008571-199310000-00003 .
• Yamazaki H, Inoue K, Mimura M, Oda Y, Guengerich FP, Shimada T . 7-Ethoxycoumarin O-deethylation catalyzed by cytochromes P450 1A2 and 2E1 in human liver microsomes . Biochemical Pharmacology . 51 . 3 . 313–319 . February 1996 . 8573198 . 10.1016/0006-2952(95)02178-7 .
• Hakkola J, Raunio H, Purkunen R, Pelkonen O, Saarikoski S, Cresteil T, Pasanen M . Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy . Biochemical Pharmacology . 52 . 2 . 379–383 . July 1996 . 8694864 . 10.1016/0006-2952(96)00216-X .
• Guengerich FP, Johnson WW . 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 . 14741–14750 . December 1997 . 9398194 . 10.1021/bi9719399 .
• Wacke R, Kirchner A, Prall F, Nizze H, Schmidt W, Fischer U, Nitschke FP, Adam U, Fritz P, Belloc C, Drewelow B . Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis . Pancreas . 16 . 4 . 521–528 . May 1998 . 9598815 . 10.1097/00006676-199805000-00011 . 24670684 .
• Macé K, Bowman ED, Vautravers P, Shields PG, Harris CC, Pfeifer AM . Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues . European Journal of Cancer . 34 . 6 . 914–920 . May 1998 . 9797707 . 10.1016/S0959-8049(98)00034-3 .
• Huang JD, Guo WC, Lai MD, Guo YL, Lambert GH . Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese . Drug Metabolism and Disposition . 27 . 1 . 98–101 . January 1999 . 9884316 .
• Tatemichi M, Nomura S, Ogura T, Sone H, Nagata H, Esumi H . Mutagenic activation of environmental carcinogens by microsomes of gastric mucosa with intestinal metaplasia . Cancer Research . 59 . 16 . 3893–3898 . August 1999 . 10463577 .

Notes and References

1. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW . 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 . January 2004 . 15128046 . 10.1097/00008571-200401000-00001 . 18448751 .
2. Jaiswal AK, Nebert DW, McBride OW, Gonzalez FJ . 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 . 1987 . 3681487 .
3. Web site: Entrez Gene: cytochrome P450. 30 August 2017. 10 May 2009. https://web.archive.org/web/20090510093747/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1544. live.
4. Westphal C, Konkel A, Schunck WH . CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? . Prostaglandins & Other Lipid Mediators . 96 . 1–4 . 99–108 . November 2011 . 21945326 . 10.1016/j.prostaglandins.2011.09.001 .
5. Fleming I . The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease . Pharmacological Reviews . 66 . 4 . 1106–1140 . October 2014 . 25244930 . 10.1124/pr.113.007781 . free .
6. Zhang G, Kodani S, Hammock BD . Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer . Progress in Lipid Research . 53 . 108–123 . January 2014 . 24345640 . 3914417 . 10.1016/j.plipres.2013.11.003 .
7. He J, Wang C, Zhu Y, Ai D . Soluble epoxide hydrolase: A potential target for metabolic diseases . Journal of Diabetes . 8 . 3 . 305–313 . May 2016 . 26621325 . 10.1111/1753-0407.12358 . free .
8. Wagner K, Vito S, Inceoglu B, Hammock BD . The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling . Prostaglandins & Other Lipid Mediators . 113–115 . 2–12 . October 2014 . 25240260 . 4254344 . 10.1016/j.prostaglandins.2014.09.001 .
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 . 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 . June 2014 . 24634501 . 4031946 . 10.1194/jlr.M047357 . free .
10. Fontana RJ, Lown KS, Paine MF, Fortlage L, Santella RM, Felton JS, Knize MG, Greenberg A, Watkins PB . Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers . Gastroenterology . 117 . 1 . 89–98 . July 1999 . 10381914 . 10.1016/S0016-5085(99)70554-8 . free .
11. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H . Coffee, CYP1A2 genotype, and risk of myocardial infarction . JAMA . 295 . 10 . 1135–1141 . March 2006 . 16522833 . 10.1001/jama.295.10.1135 . free .
12. Web site: Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Center for Drug Evaluation and Research. www.fda.gov. en. 1 June 2016. 10 May 2016. https://web.archive.org/web/20160510152158/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#classInhibit. live.
13. Sousa MC, Braga RC, Cintra BA, de Oliveira V, Andrade CH . In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9. 2013. 10.1016/j.foodres.2012.09.027 . Food Research International. 50. 102–110. free.
14. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. FDA. 26 May 2021. 22 June 2020. 4 November 2020. https://web.archive.org/web/20201104173036/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. live.
15. Alkattan A, Alsalameen E . 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 . June 2021 . 33931001 . 10.1080/17425255.2021.1925249 . 233470717 .
16. Web site: Flockhart DA . 2007 . Drug Interactions Flockhart Table . . 22 June 2020 . 30 August 2007 . https://web.archive.org/web/20070830145407/http://medicine.iupui.edu/flockhart/ . live .
17. http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals
18. Book: Ninety percent of melatonin is metabolized in the liver primarily by the enzyme CYP1A2 . Savage RA, Zafar N, Yohannan S, Miller JM . Melatonin . article-35398 . StatPearls Publishing . Treasure Island (FL) . 2021 . 30521244 . 15 November 2021 . 21 June 2021 . https://web.archive.org/web/20210621013101/https://www.ncbi.nlm.nih.gov/books/NBK534823/ . live .
19. Web site: Erlotinib . Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1 . 10 April 2018 . 24 December 2019 . https://web.archive.org/web/20191224052924/https://www.drugs.com/ppa/erlotinib.html . live .
20. 2017 . Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents . European Journal of Pharmaceutical Sciences. 109 . 182–190 . 10.1016/j.ejps.2017.07.034 . 5656517 . 28774812 . Li G, Simmler C, Chen L, Nikolic D, Chen S, Pauli GF, Van Breemen RB .
21. Dostalek M, Pistovcakova J, Jurica J, Sulcova A, Tomandl J . 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 Palacky, Olomouc, Czechoslovakia . 155 . 3 . 253–257 . September 2011 . 22286810 . 10.5507/bp.2011.047 . free . 10.1.1.660.364 .
22. Web site: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers . U.S. Food and Drug Administration . 9 February 2019 . 16 December 2019 . 10 May 2016 . https://web.archive.org/web/20160510152158/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm . live .
23. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD . The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo . Clinical Pharmacology and Therapeutics . 75 . 1 . 89–100 . January 2004 . 14749695 . 10.1016/j.clpt.2003.09.013 . 8375888 .
24. Briguglio M, Hrelia S, Malaguti M, Serpe L, Canaparo R, Dell'Osso B, Galentino R, De Michele S, Dina CZ, Porta M, Banfi G . Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles . Pharmaceutics . 10 . 4 . 277 . December 2018 . 30558213 . 6321138 . 10.3390/pharmaceutics10040277 . free .
25. Web site: Verapamil: Drug information. Lexicomp . UpToDate . 13 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 . 13 January 2019 . https://web.archive.org/web/20190113232158/https://www.uptodate.com/contents/verapamil-drug-information . live .
26. Fuhr U, Klittich K, Staib AH . 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 . 431–436 . April 1993 . 8485024 . 1381556 . 10.1111/j.1365-2125.1993.tb04162.x .
27. 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 . European Journal of Clinical Pharmacology . 57 . 11 . 799–804 . January 2002 . 11868802 . 10.1007/s00228-001-0396-3 . 19299097 .
28. Zhao Y, Hellum BH, Liang A, Nilsen OG . Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs . Phytotherapy Research . 29 . 6 . 825–834 . June 2015 . 25640685 . 10.1002/ptr.5285 . 24002845 .
29. Thai C, Tayo B, Critchley D . A Phase 1 Open-Label, Fixed-Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects . Clinical Pharmacology in Drug Development . 10 . 11 . 1279–1289 . November 2021 . 33951339 . 8596598 . 10.1002/cpdd.950 .