Biology:CYP1A2

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Short description: Enzyme in the human body


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 (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.[5][8][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 cited epoxides[8] 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.[10]

Effect of diet

Expression of CYP1A2 appears to be induced by various dietary constituents.[11] 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.[12]

CYP1A2 is also 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).[13]

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.[14]
  • 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.[14]
  • 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.[14]
Substrates Inhibitors Inducers
Strong:

Moderate

Weak

Unspecified potency:

Moderate inducers:[16]

Unspecified potency:

See also

  • Cytochrome P450 oxidase

References

  1. ↑ "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. doi:10.1097/00008571-200401000-00001. PMID 15128046. 
  2. ↑ "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. PMID 3681487. 
  3. ↑ "Entrez Gene: cytochrome P450". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1544. 
  4. ↑ "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators 96 (1–4): 99–108. November 2011. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326. 
  5. ↑ 5.0 5.1 "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. doi:10.1124/pr.113.007781. PMID 25244930. 
  6. ↑ "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research 53: 108–123. January 2014. doi:10.1016/j.plipres.2013.11.003. PMID 24345640. 
  7. ↑ "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–313. May 2016. doi:10.1111/1753-0407.12358. PMID 26621325. 
  8. ↑ 8.0 8.1 8.2 "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators 113-115: 2–12. October 2014. doi:10.1016/j.prostaglandins.2014.09.001. PMID 25240260. 
  9. ↑ "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. doi:10.1194/jlr.M047357. PMID 24634501. 
  10. ↑ Template:NCBI RefSeq
  11. ↑ "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. doi:10.1016/S0016-5085(99)70554-8. PMID 10381914. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "South Asians and Europeans react differently to common drugs", University of Sydney Faculty of Pharmacy News, 17 October 2011, http://sydney.edu.au/news/pharm/1311.html?newsstoryid=7969 
  13. ↑ "Coffee, CYP1A2 genotype, and risk of myocardial infarction". JAMA 295 (10): 1135–1141. March 2006. doi:10.1001/jama.295.10.1135. PMID 16522833. 
  14. ↑ 14.0 14.1 14.2 Center for Drug Evaluation and Research. "Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers" (in en). https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#classInhibit. 
  15. ↑ 15.0 15.1 15.2 15.3 "In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9". Food Research International 50: 102–110. 2013. doi:10.1016/j.foodres.2012.09.027. 
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 16.13 16.14 16.15 16.16 16.17 16.18 16.19 16.20 16.21 "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. 26 May 2021. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
  17. ↑ "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. doi:10.1080/17425255.2021.1925249. PMID 33931001. 
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18 18.19 18.20 18.21 18.22 18.23 18.24 18.25 18.26 18.27 18.28 18.29 18.30 18.31 18.32 18.33 18.34 18.35 18.36 18.37 18.38 18.39 18.40 18.41 "Drug Interactions Flockhart Table". Indiana University School of Medicine. 2007. https://drug-interactions.medicine.iu.edu/Home.aspx. 
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 Swedish environmental classification of pharmaceuticals - FASS (drug catalog) - Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
  20. ↑ "article-35398". Melatonin. Treasure Island (FL): StatPearls Publishing. 2021. http://www.ncbi.nlm.nih.gov/books/NBK534823/. Retrieved 15 November 2021. "Ninety percent of melatonin is metabolized in the liver primarily by the enzyme CYP1A2" 
  21. ↑ "Erlotinib". https://www.drugs.com/ppa/erlotinib.html. "Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1" 
  22. ↑ 22.0 22.1 "Verapamil: Drug information. Lexicomp". https://www.uptodate.com/contents/verapamil-drug-information. "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" 
  23. ↑ "Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents". European Journal of Pharmaceutical Sciences 109: 182–190. 2017. doi:10.1016/j.ejps.2017.07.034. PMID 28774812. 
  24. ↑ "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. 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. 9 February 2019. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. 
  26. ↑ "The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo". Clinical Pharmacology and Therapeutics 75 (1): 89–100. January 2004. doi:10.1016/j.clpt.2003.09.013. PMID 14749695. 
  27. ↑ 27.0 27.1 "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics 10 (4): 277. December 2018. doi:10.3390/pharmaceutics10040277. PMID 30558213. 
  28. ↑ "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. doi:10.1111/j.1365-2125.1993.tb04162.x. PMID 8485024. 
  29. ↑ "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. doi:10.1007/s00228-001-0396-3. PMID 11868802. 
  30. ↑ "Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs". Phytotherapy Research 29 (6): 825–834. June 2015. doi:10.1002/ptr.5285. PMID 25640685. 
  31. ↑ "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. doi:10.1002/cpdd.950. PMID 33951339. 

Further reading

External links

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




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