Cytochrome P450, family 1, member A1

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CYP1A1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CYP1A1, AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX, CYPIA1, cytochrome P450 family 1 subfamily A member 1
External IDs OMIM: 108330 MGI: 88588 HomoloGene: 68062 GeneCards: 1543
RNA expression pattern
PBB GE CYP1A1 205749 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000499
NM_001319216
NM_001319217

NM_001136059
NM_009992

RefSeq (protein)

NP_000490.1

NP_001129531.1
NP_034122.1

Location (UCSC) Chr 15: 74.72 – 74.73 Mb Chr 9: 57.7 – 57.7 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein[1] that in humans is encoded by the CYP1A1 gene.[2] The protein is a member of the cytochrome P450 superfamily of enzymes.[3]

Function[edit]

Metabolism of xenobiotics and drugs[edit]

CYP1A1 is involved in phase I xenobiotic and drug metabolism (one substrate of it is theophylline). It is inhibited by fluoroquinolones and macrolides and induced by aromatic hydrocarbons.[4]

CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (polycyclic aromatic hydrocarbons, PAH), for example, benzo(a)pyrene (BP), by transforming it to an epoxide. In this reaction, the oxidation of benzo[a]pyrene is catalysed by CYP1A1 to form BP-7,8-epoxide, which can be further oxidized by epoxide hydrolase (EH) to form BP-7,8-dihydrodiol. Finally CYP1A1 catalyses this intermediate to form BP-7,8-dihydrodiol-9,10-epoxide, which is the ultimate carcinogen.[4]

However, an in vivo experiment with gene-deficient mice has found that the hydroxylation of benzo(a)pyrene by CYP1A1 can have an overall protective effect on the DNA, rather than contributing to potentially carcinogenic DNA modifications. This effect is likely due to the fact that CYP1A1 is highly active in the intestinal mucosa, and thus inhibits infiltration of ingested benzo(a)pyrene carcinogen into the systemic circulation.[5]

CYP1A1 metabolism of various foreign agents to carcinogens has been implicated in the formation of various types of human cancer.[6][7]

Metabolism of endogenous agents[edit]

CYP1A1 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. CYP1A1 has monoxygenase activity 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).[8] 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.[9][10][11][12] 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][12][13] 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. CYP1A1 is one of the main extra-hepatic cytochrome P450 enzymes; it is not regarded as being a major contributor to forming the cited epoxides[12] but could act locally in certain tissues such as the intestine and in certain cancers to do so.

Regulation[edit]

The expression of the CYP1A1 gene, along with that of CYP1A2/1B1 genes, is regulated by a heterodimeric transcription factor that consist of the aryl hydrocarbon receptor, a ligand activated transcription factor, and the aryl hydrocarbon receptor nuclear translocator.[14] In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (TLR2),[15] which recognizes bacterial surface structures such as lipoteichoic acid.

Polymorphisms[edit]

Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:[16][17][18][19]

  • M1, TC substitution at nucleotide 3801 in the 3'-non-coding region
  • M2, AG substitution at nucleotide 2455 leading to an amino acid change of isoleucine to valine at codon 462
  • M3, TC substitution at nucleotide 3205 in the 3'-non-coding region
  • M4, CA substitution at nucleotide 2453 leading to an amino acid change of threonine to asparagine at codon 461

The highly inducible forms of CYP1A1 are associated with an increased risk of lung cancer in smokers. (Reference = Kellerman et al., New Eng J Med 1973:289;934-937) Light smokers with the susceptible genotype CYP1A1 have a sevenfold higher risk of developing lung cancer compared to light smokers with the normal genotype.

References[edit]

  1. ^ Kawajiri K (1999). "CYP1A1". IARC Scientific Publications (148): 159–72. PMID 10493257. 
  2. ^ 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. 
  3. ^ Smith G, Stubbins MJ, Harries LW, Wolf CR (Dec 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157. 
  4. ^ a b Beresford AP (1993). "CYP1A1: friend or foe?". Drug Metabolism Reviews 25 (4): 503–17. doi:10.3109/03602539308993984. PMID 8313840. 
  5. ^ Uno S, Dalton TP, Derkenne S, Curran CP, Miller ML, Shertzer HG, Nebert DW (May 2004). "Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation". Molecular Pharmacology 65 (5): 1225–37. doi:10.1124/mol.65.5.1225. PMID 15102951. 
  6. ^ Badal S, Delgoda R (Jul 2014). "Role of the modulation of CYP1A1 expression and activity in chemoprevention". Journal of Applied Toxicology 34 (7): 743–53. doi:10.1002/jat.2968. PMID 24532440. 
  7. ^ Go RE, Hwang KA, Choi KC (Mar 2015). "Cytochrome P450 1 family and cancers". The Journal of Steroid Biochemistry and Molecular Biology 147: 24–30. doi:10.1016/j.jsbmb.2014.11.003. PMID 25448748. 
  8. ^ 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. 
  9. ^ a b 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. 
  10. ^ 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. PMC 3914417. PMID 24345640. 
  11. ^ He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–13. doi:10.1111/1753-0407.12358. PMID 26621325. 
  12. ^ a b c 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. PMC 4254344. PMID 25240260. 
  13. ^ 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. PMC 4031946. PMID 24634501. 
  14. ^ Ma Q, Lu AY (Jul 2007). "CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies". Drug Metabolism and Disposition 35 (7): 1009–16. doi:10.1124/dmd.107.015826. PMID 17431034. 
  15. ^ Do KN, Fink LN, Jensen TE, Gautier L, Parlesak A (2012). "TLR2 controls intestinal carcinogen detoxication by CYP1A1". PloS One 7 (3): e32309. doi:10.1371/journal.pone.0032309. PMC 3307708. PMID 22442665. 
  16. ^ Petersen DD, McKinney CE, Ikeya K, Smith HH, Bale AE, McBride OW, Nebert DW (Apr 1991). "Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP". American Journal of Human Genetics 48 (4): 720–5. PMC 1682951. PMID 1707592. 
  17. ^ Cosma G, Crofts F, Taioli E, Toniolo P, Garte S (1993). "Relationship between genotype and function of the human CYP1A1 gene". Journal of Toxicology and Environmental Health 40 (2-3): 309–16. doi:10.1080/15287399309531796. PMID 7901425. 
  18. ^ Crofts F, Taioli E, Trachman J, Cosma GN, Currie D, Toniolo P, Garte SJ (Dec 1994). "Functional significance of different human CYP1A1 genotypes". Carcinogenesis 15 (12): 2961–3. doi:10.1093/carcin/15.12.2961. PMID 8001264. 
  19. ^ Kiyohara C, Hirohata T, Inutsuka S (Jan 1996). "The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene". Japanese Journal of Cancer Research 87 (1): 18–24. doi:10.1111/j.1349-7006.1996.tb00194.x. PMID 8609043. 

Further reading[edit]

  • 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. 
  • Masson LF, Sharp L, Cotton SC, Little J (May 2005). "Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: a HuGE review". American Journal of Epidemiology 161 (10): 901–15. doi:10.1093/aje/kwi121. PMID 15870154. 
  • Hildebrandt AG, Schwarz D, Krusekopf S, Kleeberg U, Roots I (2007). "Recalling P446. P4501A1 (CYP1A1) opting for clinical application". Drug Metabolism Reviews 39 (2-3): 323–41. doi:10.1080/03602530701498026. PMID 17786624.