Kim Sang K, Novak Raymond F
Institute of Environmental Health Sciences, Wayne State University, 2727 Second Avenue, Room 4000, Detroit, MI 48201, USA.
Pharmacol Ther. 2007 Jan;113(1):88-120. doi: 10.1016/j.pharmthera.2006.07.004. Epub 2006 Nov 13.
Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption produce changes in hepatic drug metabolizing enzyme gene and protein expression. This difference in expression alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants and therapeutic agents, potentially impacting the efficacy and safety of therapeutic agents, and/or resulting in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone- and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory has reported that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450 (CYP), glutathione S-transferases (GST) and microsomal epoxide hydrolase (mEH), through receptors which are members of the large receptor tyrosine kinase (RTK) family, and by downstream effectors such as phosphatidylinositol 3-kinase, mitogen activated protein kinase (MAPK), Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR), and the p70 ribosomal protein S6 kinase (p70S6 kinase). Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how disease affects these signaling pathways, components, and ultimately gene expression and translational control.
内源性因素，包括激素、生长因子和细胞因子，在生理和病理生理条件下对肝脏药物代谢酶表达的调节中发挥着重要作用。糖尿病、禁食、肥胖、蛋白质 - 热量营养不良和长期饮酒会导致肝脏药物代谢酶基因和蛋白质表达发生变化。这种表达差异会改变外源性物质的代谢，包括前致癌物、致癌物、毒物和治疗药物，可能影响治疗药物的疗效和安全性，和/或导致药物相互作用。尽管对外源性物质调节药物代谢酶的机制已进行了深入研究，但对于响应激素和细胞因子调节药物代谢酶基因和蛋白质表达的细胞信号通路和成分了解较少。然而，最近的研究结果表明，几种细胞信号通路参与了激素和生长因子介导的药物代谢酶调节。我们实验室报告称，胰岛素和生长因子通过大受体酪氨酸激酶（RTK）家族成员的受体以及磷脂酰肌醇3激酶、丝裂原活化蛋白激酶（MAPK）、Akt/蛋白激酶B（PKB）、雷帕霉素靶蛋白（mTOR）和p70核糖体蛋白S6激酶（p70S6激酶）等下游效应器来调节药物代谢酶基因和蛋白质表达，包括细胞色素P450（CYP）、谷胱甘肽S - 转移酶（GST）和微粒体环氧化物水解酶（mEH）。在此，我们综述了当前关于响应胰岛素和生长因子调节药物代谢酶基因和蛋白质表达的信号通路的知识，目的是增进我们对疾病如何影响这些信号通路、成分以及最终基因表达和翻译控制的理解。
