Ethanol-mediated regulation of cytochrome P450 2A6 expression in monocytes: role of oxidative stress-mediated PKC/MEK/Nrf2 pathway.
Ethanol-mediated regulation of cytochrome P450 2A6 expression in monocytes: role of oxidative stress-mediated PKC/MEK/Nrf2 pathway.
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DOI：
10.1371/journal.pone.0035505
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Jin M;Kumar A;Kumar S
已知细胞色素 P450 2A6 (CYP2A6) 会代谢烟草的主要成分尼古丁，从而导致有毒代谢物的产生并诱导氧化应激，从而导致肝损伤和肺癌。最近，我们发现 CYP2A6 受乙醇诱导，将尼古丁代谢为可替宁和其他代谢物，导致 U937 单核细胞中产生活性氧 (ROS)。然而，乙醇诱导 CYP2A6 的机制尚不清楚。在本研究中，我们研究了 PKC/Nrf2 通路（蛋白激酶 C 介导的磷酸化和核红细胞 2 相关因子 2 转位至细胞核）在乙醇介导的 CYP2A6 诱导中的作用。我们的结果表明，100 mM 乙醇显着诱导 CYP2A6 mRNA 和蛋白质（~150%）并增加 ROS 形成，并且基因表达和 ROS 的诱导均被 CYP2E1 抑制剂（二烯丙基硫醚）或抗氧化剂（维生素 C）处理完全阻断。结果表明氧化应激在 CYP2A6 表达调节中的作用。随后，我们研究了 Nrf2 通路在氧化应激介导的 U937 单核细胞 CYP2A6 表达调节中的作用。我们的结果表明，丁基羟基苯甲醚（核 Nrf2 的稳定剂）可将 CYP2A6 水平提高>200%。 Staurosporine 是一种 PKC 抑制剂，可完全消除乙醇诱导的 CYP2A6 表达。此外，我们的结果表明，丝裂原激活蛋白激酶激酶 (MEK) (U0126) 的特异性抑制剂完全消除了乙醇介导的 CYP2A6 诱导和 Nrf2 易位。总体而言，这些结果表明，乙醇代谢产生的 CYP2E1 介导的氧化应激通过 PKC/MEK 途径将 Nrf2 易位到细胞核中，导致单核细胞中 CYP2A6 的诱导。单核细胞中 CYP2A6 水平的增加预计会通过 CYP2A6 介导的尼古丁代谢进一步增加吸烟者的氧化应激。因此，这项研究具有临床意义，因为吸烟者，尤其是艾滋病毒感染者中饮酒的发生率很高。
Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (∼150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol-induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV-infected individuals.
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