Institute of Molecular Biology and Biophysics SB RAMS, Timakova Str. 2, Novosibirsk, 630117, Russia.
J Physiol Biochem. 2011 Dec;67(4):499-510. doi: 10.1007/s13105-011-0095-1. Epub 2011 Apr 20.
Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) is known to metabolize anthropogenic xenobiotics to carcinogenic and mutagenic compounds. CYP1A1 transcriptional activation is regulated via the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway. CYP1A2 activation may occur through the AhR-dependent or AhR-independent signal transduction pathways. We used male Wistar rats to explore possible mechanisms of CYP1A activation induced by exposure to cold and the effects of the protein-tyrosine kinase inhibitors genistein, herbimycin A, and geldanamycin on the properties of hepatic CYP1A1 and CYP1A2 proteins following exposure to cold and to classic CYP1A inducers. The molecular mechanisms of cold-induced CYP1A1 and CYP1A2 activation are different. The CYP1A2 activation apparently occurs at the post-transcriptional level. The CYP1A1 activation, whether caused by exposure to cold or by classic CYP1A inducers, is AhR-dependent and occurs at the transcriptional level. Protein tyrosine kinase inhibitors have no effect on benzo(a)pyrene-induced CYP1A expression but alter cold-induced CYP1A1 activity and the CYP1A1 mRNA level. Thus, treatment with herbimycin A or geldanamycin leads to an increase in CYP1A1 activity, while treatment with genistein increases CYP1A1 mRNA expression and decreases CYP1A2 activity. These data elucidate the molecular mechanisms of cold-induced CYP1A activation and the role of protein kinases in the regulation of CYP1A during exposure to cold. Our results can also help identify the differences between the molecular mechanisms underlying the effects of the classic CYP1A inducers and the effects of cooling.
细胞色素 P4501A（CYP1A1 和 CYP1A2 酶）已知将人为外源化学物质代谢为致癌和致突变化合物。CYP1A1 的转录激活受芳基烃受体（AhR）依赖性信号转导途径调节。CYP1A2 的激活可能通过 AhR 依赖性或 AhR 非依赖性信号转导途径发生。我们使用雄性 Wistar 大鼠来探索暴露于寒冷后 CYP1A 激活的可能机制，以及蛋白酪氨酸激酶抑制剂金雀异黄素、草霉素 A 和格尔德霉素对暴露于寒冷和经典 CYP1A 诱导剂后肝 CYP1A1 和 CYP1A2 蛋白特性的影响。冷诱导 CYP1A1 和 CYP1A2 激活的分子机制不同。CYP1A2 的激活显然发生在转录后水平。CYP1A1 的激活，无论是由暴露于寒冷还是由经典 CYP1A 诱导剂引起的，都是 AhR 依赖性的，并发生在转录水平。蛋白酪氨酸激酶抑制剂对苯并（a）芘诱导的 CYP1A 表达没有影响，但改变冷诱导的 CYP1A1 活性和 CYP1A1 mRNA 水平。因此，草霉素 A 或格尔德霉素的处理导致 CYP1A1 活性增加，而金雀异黄素的处理增加 CYP1A1 mRNA 表达并降低 CYP1A2 活性。这些数据阐明了冷诱导 CYP1A 激活的分子机制以及蛋白激酶在暴露于寒冷时调节 CYP1A 的作用。我们的结果还可以帮助识别经典 CYP1A 诱导剂的作用和冷却的作用的分子机制之间的差异。
