CYP1A2

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.{{cite web| title = Entrez Gene: cytochrome P450| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1544| access-date = 30 August 2017| archive-date = 10 May 2009| archive-url = https://web.archive.org/web/20090510093747/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1544| url-status = live}}

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).{{cite journal | vauthors = Westphal C, Konkel A, Schunck WH | title = CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? | journal = Prostaglandins & Other Lipid Mediators | volume = 96 | issue = 1–4 | pages = 99–108 | date = November 2011 | pmid = 21945326 | doi = 10.1016/j.prostaglandins.2011.09.001 }}

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.{{cite journal | vauthors = Fleming I | title = The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease | journal = Pharmacological Reviews | volume = 66 | issue = 4 | pages = 1106–1140 | date = October 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 | doi-access = free }}{{cite journal | vauthors = Zhang G, Kodani S, Hammock BD | title = Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer | journal = Progress in Lipid Research | volume = 53 | pages = 108–123 | date = January 2014 | pmid = 24345640 | pmc = 3914417 | doi = 10.1016/j.plipres.2013.11.003 }}{{cite journal | vauthors = He J, Wang C, Zhu Y, Ai D | title = Soluble epoxide hydrolase: A potential target for metabolic diseases | journal = Journal of Diabetes | volume = 8 | issue = 3 | pages = 305–313 | date = May 2016 | pmid = 26621325 | doi = 10.1111/1753-0407.12358 | doi-access = free }}{{cite journal | vauthors = Wagner K, Vito S, Inceoglu B, Hammock BD | title = The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling | journal = Prostaglandins & Other Lipid Mediators | volume = 113–115 | pages = 2–12 | date = October 2014 | pmid = 25240260 | pmc = 4254344 | doi = 10.1016/j.prostaglandins.2014.09.001 }} 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.{{cite journal | vauthors = 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 | title = Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway | journal = Journal of Lipid Research | volume = 55 | issue = 6 | pages = 1150–1164 | date = June 2014 | pmid = 24634501 | pmc = 4031946 | doi = 10.1194/jlr.M047357 |doi-access=free }} 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.{{NCBI RefSeq|title=PharmVar |url=https://www.pharmvar.org/gene/CYP1A2 |access-date=20 May 2020}}

Expression of CYP1A2 appears to be induced by various dietary constituents.{{cite journal | vauthors = Fontana RJ, Lown KS, Paine MF, Fortlage L, Santella RM, Felton JS, Knize MG, Greenberg A, Watkins PB | title = Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers | journal = Gastroenterology | volume = 117 | issue = 1 | pages = 89–98 | date = July 1999 | pmid = 10381914 | doi = 10.1016/S0016-5085(99)70554-8 | doi-access = free }} 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.{{citation|vauthors=Sanday K|url=http://sydney.edu.au/news/pharm/1311.html?newsstoryid=7969|work=University of Sydney Faculty of Pharmacy News|title=South Asians and Europeans react differently to common drugs|date=17 October 2011|access-date=24 October 2011|archive-date=9 March 2014|archive-url=https://web.archive.org/web/20140309144021/http://sydney.edu.au/news/pharm/1311.html?newsstoryid=7969|url-status=live}}

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).{{cite journal | vauthors = Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H | title = Coffee, CYP1A2 genotype, and risk of myocardial infarction | journal = JAMA | volume = 295 | issue = 10 | pages = 1135–1141 | date = March 2006 | pmid = 16522833 | doi = 10.1001/jama.295.10.1135 | doi-access = free }}

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.{{cite web|url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#classInhibit|title=Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|last=Center for Drug Evaluation and Research|website=www.fda.gov|language=en|access-date=1 June 2016|archive-date=10 May 2016|archive-url=https://web.archive.org/web/20160510152158/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#classInhibit|url-status=dead}}
• 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.

• Drug metabolism

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• {{UCSC gene info|CYP1A2}}
• {{PDBe-KB2|P05177|Cytochrome P450 1A2}}

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Category:Pharmacogenomics