p450 - publications

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1. Curr Drug Metab. 2012 Apr 9. [Epub ahead of print]

Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults
in the liver.

Abu-Bakar A, Hakkola J, Juvonen R, Rahnasto-Rilla M, Raunio H, Lang MA.

Entox, the University of Queensland, 39 Kessels Road, Coopers Plains, 4108
Queensland, Australia. a.abubakar@uq.edu.au.

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 stabilization mediated by interaction
of the stress activated hnRNP A1 with the 3'UTR of the CYP2A5/CYP2A6 mRNA. The
up-regulation via enhanced transcription combined with mRNA stabilization, 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.

PMID: 22497566 [PubMed - as supplied by publisher]