Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, United States.
Toxicology. 2010 Oct 29;276(3):184-91. doi: 10.1016/j.tox.2010.08.005. Epub 2010 Aug 13.
Chlorpyrifos, an organophophorothioate insecticide, is bioactivated to the neurotoxic metabolite, chlorpyrifos-oxon (CPO) by cytochromes P450 (CYPs). To determine the variability in chlorpyrifos bioactivation, CPO production by human liver microsomes from 17 individual donors was compared relative to phenotype and genotype. CPO production varied over 14-fold between individuals in incubations utilizing 20 μM chlorpyrifos as substrate, while CPO production varied 57-fold in incubations with 100 μM chlorpyrifos. For all but two samples, the formation of the less toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCP), was greater than CPO production. TCP production varied 9-fold in incubations utilizing 20 μM chlorpyrifos as substrate and 19-fold using 100 μM chlorpyrifos. Chlorpyrifos metabolism by individual human liver microsomes was significantly correlated with CYP2B6, CYP2C19 and CYP3A4 related activity. CPO formation was best correlated with CYP2B6 related activity at low (20 μM) chlorpyrifos concentrations while CYP3A4 related activity was best correlated with CPO formation at high concentrations (100 μM) of chlorpyrifos. TCP production was best correlated with CYP3A4 activity at all substrate concentrations of chlorpyrifos. The production of both CPO and TCP was significantly lower at a concentration of 20 μM chlorpyrifos as compared to 100 μM chlorpyrifos. Calculations of percent total normalized rates (% TNR) and the chemical inhibitors ketoconazole and ticlopidine were used to confirm the importance of CYP2B6, CYP2C19, and CYP3A4 for the metabolism of chlorpyrifos. The combination of ketoconazole and ticlopidine inhibited the majority of TCP and CPO formation. CPO formation did not differ by CYP2B6 genotype. Individual variations in CPO production may need to be considered in determining the risk of chlorpyrifos poisoning.
毒死蜱是一种有机磷硫代酯杀虫剂，在细胞色素 P450（CYPs）的作用下生物转化为神经毒性代谢物氧乐果（CPO）。为了确定毒死蜱生物活化的可变性，比较了来自 17 个个体供体的人肝微粒体中 CPO 的产生与表型和基因型。在利用 20μM 毒死蜱作为底物的孵育中，个体间 CPO 的产生差异超过 14 倍，而在利用 100μM 毒死蜱的孵育中，CPO 的产生差异超过 57 倍。除了两个样本外，毒性较小的代谢物 3,5,6-三氯-2-吡啶醇（TCP）的形成量大于 CPO 的产生量。在利用 20μM 毒死蜱作为底物的孵育中，TCP 的产生量差异为 9 倍，而在利用 100μM 毒死蜱的孵育中，TCP 的产生量差异为 19 倍。个体人肝微粒体对毒死蜱的代谢与 CYP2B6、CYP2C19 和 CYP3A4 相关活性显著相关。在低浓度（20μM）毒死蜱时，CPO 的形成与 CYP2B6 相关活性的相关性最好，而在高浓度（100μM）毒死蜱时，CPO 的形成与 CYP3A4 相关活性的相关性最好。在所有毒死蜱底物浓度下，TCP 的产生与 CYP3A4 活性的相关性最好。与 100μM 毒死蜱相比，20μM 毒死蜱的 CPO 和 TCP 的产生量显著降低。用归一化总速率的百分比（%TNR）和化学抑制剂酮康唑和噻氯匹定计算来确认 CYP2B6、CYP2C19 和 CYP3A4 对毒死蜱代谢的重要性。酮康唑和噻氯匹定的联合使用抑制了大部分 TCP 和 CPO 的形成。CPO 的形成与 CYP2B6 基因型无关。在确定毒死蜱中毒的风险时，可能需要考虑 CPO 产生的个体差异。
