University of Queensland, 39 Kessels Road, Coopers Plains, 4108 Queensland, Australia.
Curr Drug Metab. 2013 Jan;14(1):137-50.
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.
小鼠肝细胞色素 P450（CYP）2A5 及其人类同源物 CYP2A6 催化多种药物和毒素的代谢，如卤烷和黄曲霉毒素 B1。这些酶分别因其对这些化合物的高亲和力和特异性活性而被命名为“香豆素 7-羟化酶”和“尼古丁羟化酶”。胆红素是血红素的分解产物，已被认为是这两种酶的内源性底物。独特的是，CYP2A5 和 CYP2A6 在与肝损伤相关的病理条件下被诱导，而大多数其他 CYP 酶的功能受损，这表明相应基因的调控模式异常。这些基因的调控确实很复杂，启动子与多种应激激活转录因子相互作用。Cyp2a5 启动子包含一个“应激反应”结合基序簇，与包括核因子-E2 p45 相关因子 2（Nrf2）和芳烃受体（AhR）在内的多种毒性物质的主要介质相互作用。这些相互作用对于应激条件下基因的上调至关重要。此外，通过应激激活的异质核糖核蛋白 A1（hnRNP A1）与 CYP2A5/CYP2A6 mRNA 的 3'UTR 相互作用介导的 mRNA 稳定化，也可以实现转录的升高。在一些应激情况下，通过增强转录与 mRNA 稳定化的上调会导致特别强烈、快速和持久的反应。本综述汇集了我们实验室和其他实验室在毒理学应激下 Cyp2a5/CYP2A6 基因调控以及它们的催化活性的毒理学意义方面的研究成果，这些成果可能为这些酶在与肝毒性相关的功能作用提供线索。
