title: Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver.
abstract: The mouse hepatic cytochrome P450 (CYP) 2A5 and its human orthologue CYP2A6 catalyse the metabolism of a number of drugs and toxins, such as halothane and aflatoxin B1. The enzymes are named "Coumarin 7-hydroxylase" and "Nicotine Hydroxylase", respectively, by virtue of their high affinity and specific activity towards these compounds. Bilirubin, the breakdown product of haem, has been suggested to be the endogenous substrate for both enzymes. Uniquely, CYP2A5 and CYP2A6 are induced during pathological conditions associated with liver injury when the function of most other CYP enzymes is compromised, which suggests an exceptional mode of regulation of the corresponding genes. Regulation of these genes is indeed complex where the promoters interact with multiple stress-activated transcription factors. The Cyp2a5 promoter contains a "stress-responding" cluster of binding motifs, which interact with major mediators of toxic insults including nuclear factor-E2 p45-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AhR). These interactions are crucial in the up-regulation of the genes under stress conditions. Additionally, elevated transcription is also achieved through mRNA stabilisation mediated by interaction of the stress activated heterogenous ribonucleoprotein A1 (hnRNP A1) with the 3'UTR of the CYP2A5/CYP2A6 mRNA. The up-regulation via enhanced transcription combined with mRNA stabilisation, as seen in some of the stress situations, leads to a particularly strong, fast and persistent response. This review brings together knowledge obtained from studies in our laboratories and others' on regulation of Cyp2a5/CYP2A6 genes in response to toxic insults and toxicological significance of their catalytic activities that may provide clues to a functional role of the enzymes in relation to liver toxicity.
authors.affiliation: University of Queensland, 39 Kessels Road, Coopers Plains, 4108 Queensland, Australia. a.abubakar@uq.edu.au
authors.forename: A'edah
authors.initials: A
authors.lastname: Abu-Bakar
authors.forename: Jukka
authors.initials: J
authors.lastname: Hakkola
authors.forename: Risto
authors.initials: R
authors.lastname: Juvonen
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto-Rilla
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.forename: Matti A
authors.initials: MA
authors.lastname: Lang
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000473:pathology*; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology*; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D014157:Transcription Factors; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D001663:Bilirubin