Abstract
Chlorpyrifos (CPF), an organophosphorus (OP) pesticide, is bioactivated by cytochrome P450s (CYPs) to the active metabolite chlorpyrifos oxon (CPF-O). Given that human CYP2B6 has the highest intrinsic clearance (CLint) for CPF bioactivation, CYP2B6 polymorphisms may impact human susceptibility to CPF at real world environmental and occupational CPF exposure levels.CYP2B6.4,.5,.7, and .18 were over-expressed in mammalian COS-1 cells to assess the impact of CYP2B6 variants on the Km and Vmax for bioactivation of CPF. Cell lysates were incubated with CPF (0–100 μM) and the production of CPF-O was measured via HPLC analysis. CYP2B6 content was determined by western blot.CYP2B6.18 had neither detectable protein nor activity levels. The Vmax value for each remaining variant was significantly higher than wild-type (CYP2B6.1, Vmax 4.13 × 104 pmol/min/nmol CYP2B6), with CYP2B6.4,.5, and .7 having Vmax values of 4.52 × 105, 1.82 × 105, and 9.60 × 104 pmol/min/nmol CYP2B6, respectively. The Km values for these variants ranged from 0.39 to 1.09 μM and were not significantly different from wild-type. All active variants examined had significantly higher CLint than CYP2B6.1.Variants of CYP2B6 have altered capacity to bioactivate CPF and may affect individual susceptibility by altering the Vmax for CPF-O formation.
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