Evidence for the activation of organophosphate pesticides by cytochromes P450 3A4 and 2D6 in human liver microsomes

The role of specific cytochrome P450 isoforms in catalysing the oxidative b iotransformation of the organophosphorothioate pesticides parathion, chlorp yrifos and diazinon into structures that inhibit cholinesterase has been in vestigated in human liver microsomes using chemical inhibitors. Pesticides were incubated with human liver microsomes and production of the anticholin ergic oxon metabolite was investigated by the inhibition of human serum cho linesterase. Quinidine and ketoconazole at 10 mu mol/l inhibited oxidative biotransformation. Compared to control incubations (no inhibitor) where cho linesterase activity was inhibited to between 1 and 4% of control levels, i ncorporation of the CYP2D6 inhibitor quinidine into the microsomal incubati on resulted in cholinesterase activity of 50% for parathion, 38% for diazin on and 30% for chlorpyrifos. Addition of the CYP3A4 inhibitor ketoconazole to microsomal incubations resulted in 66% cholinesterase activity with diaz inon, 20% with parathion and 5% with chlorpyrifos. The unexpected finding t hat CYP2D6, as well as CYP3A4, catalysed oxidative biotransformation was co nfirmed for chlorpyrifos and parathion using microsomes prepared from a hum an lymphoblastoid cell line expressing CYP2D6. While parathion has been inv estigated only as a model compound, chlorpyrifos and diazinon are both very important, widely used pesticides and CYP2D6 appears to be an important en zyme in their bioactivation pathway. CYP2D6 is polymorphic and hence may in fluence individual susceptibility to exposure to chlorpyrifos and diazinon as well as other structurally similar pesticides. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.