Ramos S, Sultatos L
Department of Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2714, USA.
Toxicology. 1998 Nov 16;131(2-3):155-67. doi: 10.1016/s0300-483x(98)00125-5.
The majority of insecticides currently in use throughout the world belong to the class of the organophosphorus insecticides. Many of these compounds, such as the phosphorothioate insecticides, exert their mammalian toxicity only after undergoing metabolic activation by a variety of cytochrome P450 isoforms to produce their corresponding oxygen analogs (or oxons), which are potent inhibitors of the critical enzyme acetylcholinesterase. Of the many chemicals identified that can modulate cytochrome P450-dependent activities, the flavonoids represent some of the most unusual compounds in that they have been reported to both inhibit and stimulate certain activities. The present study was undertaken to determine if representative flavonoids (at in vitro concentrations of 1-100 microM) can alter the mammalian cytochrome P450-dependent biotransformation and acute toxicity of the phosphorothioate insecticide parathion. The flavonoids 5,6-benzoflavone, flavone, and quercetin had the biphasic effect of stimulating mouse hepatic microsomal parathion oxidation at a concentration of 1 microM, and inhibiting this same activity when increased to 100 microM. In contrast, 7,8-benzoflavone was only inhibitory at all concentrations examined. All the flavonoids examined except quercetin altered the ratio of activation/detoxification of parathion by mouse hepatic microsomes, but had no effect on this same ratio with human CYP1A2. These data suggest that the changes in the activation/detoxification ratio observed with mouse hepatic microsomes resulted from selective inhibition or stimulation of various cytochrome P450 isoforms rather than a flavonoid-induced alteration in the nonenzymatic rearrangement of the putative phosphooxythirane intermediate generated by cytochromes P450 from parathion. Surprisingly, however, none of the four flavonoids in the current study affected the lethality of parathion in vivo, suggesting that the flavonoid-induced alterations in cytochrome P-450-dependent metabolism of parathion documented in vitro were simply not great enough to be of any significance in vivo.
目前在世界范围内广泛使用的大多数杀虫剂属于有机磷杀虫剂类别。这些化合物中的许多，如硫代磷酸酯杀虫剂，只有在经过多种细胞色素P450同工型的代谢激活后才会对哺乳动物产生毒性，从而产生其相应的氧类似物（或氧磷），而氧磷是关键酶乙酰胆碱酯酶的强效抑制剂。在已确定的许多能够调节细胞色素P450依赖性活性的化学物质中，黄酮类化合物是一些最为独特的化合物，因为据报道它们既能抑制又能刺激某些活性。本研究旨在确定代表性黄酮类化合物（体外浓度为1 - 100微摩尔）是否能够改变硫代磷酸酯杀虫剂对硫磷的哺乳动物细胞色素P450依赖性生物转化及急性毒性。黄酮类化合物5,6 - 苯并黄酮、黄酮和槲皮素具有双相效应，在浓度为1微摩尔时刺激小鼠肝微粒体对硫磷氧化，而当浓度增加到100微摩尔时则抑制相同活性。相比之下，7,8 - 苯并黄酮在所有检测浓度下均仅具有抑制作用。除槲皮素外，所有检测的黄酮类化合物均改变了小鼠肝微粒体对硫磷的激活/解毒比率，但对人CYP1A2的相同比率没有影响。这些数据表明，在小鼠肝微粒体中观察到的激活/解毒比率变化是由于对各种细胞色素P450同工型的选择性抑制或刺激，而不是黄酮类化合物诱导的细胞色素P450从对硫磷生成的假定磷氧硫杂环丙烷中间体的非酶重排改变。然而，令人惊讶的是，本研究中的四种黄酮类化合物均未影响对硫磷在体内的致死性，这表明体外记录的黄酮类化合物诱导的对硫磷细胞色素P - 450依赖性代谢改变在体内根本没有足够大的意义。
