Hodgson Ernest, Rose Randy L
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA. ernest
Pest Manag Sci. 2008 Jun;64(6):617-21. doi: 10.1002/ps.1563.
Agrochemicals and other xenobiotics are metabolized by xenobiotic-metabolizing enzymes (XMEs) to products that may be more or less toxic than the parent chemical. In this regard, phase-I XMEs such as cytochrome P450s (CYPs) are of primary importance. Interactions at the level of metabolism may take place via either inhibition or induction of XMEs. Such interactions have often been investigated, in vitro, in experimental animals, using subcellular fractions such as liver microsomes, but seldom in humans or at the level of individual XME isoforms. The authors have been investigating the metabolism of a number of agrochemicals by human liver microsomes and recombinant CYP isoforms and have recently embarked on studies of the induction of XMEs in human hepatocytes. The insecticides chlorpyrifos, carbaryl, carbofuran and fipronil, as well as the repellant DEET, are all extensively metabolized by human liver microsomes and, although a number of CYP isoforms may be involved, CYP2B6 and CYP3A4 are usually the most important. Permethrin is hydrolyzed by esterase(s) present in both human liver microsomes and cytosol. A number of metabolic interactions have been observed. Chlorpyrifos and other phosphorothioates are potent inhibitors of the CYP-dependent metabolism of both endogenous substrates, such as testosterone and estradiol, and exogenous substrates, such as carbaryl, presumably as a result of the interaction of highly reactive sulfur, released during the oxidative desulfuration reaction, with the heme iron of CYP. The hydrolysis of permethrin in human liver can be inhibited by chlorpyrifos oxon and by carbaryl. Fipronil can inhibit testosterone metabolism by CYP3A4 and is an effective inducer of CYP isoforms in human hepatocytes.
农用化学品和其他外源性物质通过外源性物质代谢酶（XMEs）代谢为可能比母体化学物质毒性更强或更弱的产物。在这方面，I相XMEs，如细胞色素P450s（CYPs）至关重要。代谢水平的相互作用可能通过XMEs的抑制或诱导发生。此类相互作用通常在体外实验动物中，使用肝微粒体等亚细胞组分进行研究，但在人类中或个体XME同工型水平上很少进行研究。作者一直在研究人肝微粒体和重组CYP同工型对多种农用化学品的代谢情况，并且最近开始了对人肝细胞中XMEs诱导作用的研究。杀虫剂毒死蜱、西维因、克百威和氟虫腈，以及驱虫剂避蚊胺，都能被人肝微粒体广泛代谢，尽管可能涉及多种CYP同工型，但CYP2B6和CYP3A4通常最为重要。氯菊酯可被人肝微粒体和胞质溶胶中存在的酯酶水解。已观察到多种代谢相互作用。毒死蜱和其他硫代磷酸酯是内源性底物（如睾酮和雌二醇）以及外源性底物（如西维因）的CYP依赖性代谢的强效抑制剂，这可能是由于氧化脱硫反应过程中释放的高活性硫与CYP的血红素铁相互作用的结果。毒死蜱氧磷和西维因可抑制人肝中氯菊酯的水解。氟虫腈可抑制CYP3A4介导的睾酮代谢，并且是人类肝细胞中CYP同工型的有效诱导剂。
