Sams C, Mason H J, Rawbone R
Health and Safety Laboratory, Broad Lane, S3 7HQ, Sheffield, UK.
Toxicol Lett. 2000 Aug 16;116(3):217-21. doi: 10.1016/s0378-4274(00)00221-6.
The role of specific cytochrome P450 isoforms in catalysing the oxidative biotransformation of the organophosphorothioate pesticides parathion, chlorpyrifos and diazinon into structures that inhibit cholinesterase has been investigated in human liver microsomes using chemical inhibitors. Pesticides were incubated with human liver microsomes and production of the anticholinergic oxon metabolite was investigated by the inhibition of human serum cholinesterase. Quinidine and ketoconazole at 10 micromol/l inhibited oxidative biotransformation. Compared to control incubations (no inhibitor) where cholinesterase activity was inhibited to between 1 and 4% of control levels, incorporation of the CYP2D6 inhibitor quinidine into the microsomal incubation resulted in cholinesterase activity of 50% for parathion, 38% for diazinon and 30% for chlorpyrifos. Addition of the CYP3A4 inhibitor ketoconazole to microsomal incubations resulted in 66% cholinesterase activity with diazinon, 20% with parathion and 5% with chlorpyrifos. The unexpected finding that CYP2D6, as well as CYP3A4, catalysed oxidative biotransformation was confirmed for chlorpyrifos and parathion using microsomes prepared from a human lymphoblastoid cell line expressing CYP2D6. While parathion has been investigated only as a model compound, chlorpyrifos and diazinon are both very important, widely used pesticides and CYP2D6 appears to be an important enzyme in their bioactivation pathway. CYP2D6 is polymorphic and hence may influence individual susceptibility to exposure to chlorpyrifos and diazinon as well as other structurally similar pesticides.
利用化学抑制剂，在人肝微粒体中研究了特定细胞色素P450同工型在催化有机磷硫代磷酸酯农药对硫磷、毒死蜱和二嗪农氧化生物转化为抑制胆碱酯酶的结构中的作用。将农药与人肝微粒体一起孵育，并通过抑制人血清胆碱酯酶来研究抗胆碱能氧代代谢物的产生。10微摩尔/升的奎尼丁和酮康唑抑制氧化生物转化。与对照孵育（无抑制剂）相比，对照孵育中胆碱酯酶活性被抑制至对照水平的1%至4%，将CYP2D6抑制剂奎尼丁加入微粒体孵育中，对硫磷的胆碱酯酶活性为50%，二嗪农为38%，毒死蜱为30%。向微粒体孵育中加入CYP3A4抑制剂酮康唑后，二嗪农的胆碱酯酶活性为66%，对硫磷为20%，毒死蜱为5%。使用从表达CYP2D6的人淋巴母细胞系制备的微粒体，对毒死蜱和对硫磷证实了CYP2D6以及CYP3A4催化氧化生物转化这一意外发现。虽然仅将对硫磷作为模型化合物进行了研究，但毒死蜱和二嗪农都是非常重要且广泛使用的农药，CYP2D6似乎是它们生物活化途径中的一种重要酶。CYP2D6具有多态性，因此可能影响个体对毒死蜱、二嗪农以及其他结构相似农药暴露的易感性。
