Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse, and rat liver microsomes.

One of the factors determining the toxicity of chlorpyrifos (CPS), an organophosphorus (OP) insecticide, is its biotransformation. CPS can be activated by cytochrome P450 (CYP) through a desulfuration reaction to form chlorpyrifos-oxon (CPO), a potent anticholinesterase. CPS can also be detoxified by CYP through a dearylation reaction. Using pooled human liver microsomes (HLM), a K(m(app)) of 30.2 microM and V(max(app)) of 0.4 nmol/min/mg of protein was obtained for desulfuration, and a K(m(app)) of 14.2 microM and a V(max(app)) of 0.7 nmol/min/mg of protein was obtained for dearylation. These activities are lower than those obtained from rat liver microsomes. Gender differences in humans were also observed with female HLM possessing greater activity than male HLM. Use of human CYP isoforms expressed in human lymphoblastoma cells demonstrated that CYP1A2, 2B6, 2C9*1, 2C19, and 3A4 are involved in CPS metabolism. CYP2B6 has the highest desulfuration activity, whereas dearylation activity is highest for 2C19. CYP3A4 has high activity for both dearylation and desulfuration. The use of phenotyped individual HLM demonstrated that predictions of metabolic activation and/or detoxication could be made based on relative amounts of CYP2B6, 2C19, and 3A4 in the microsomes. Thus, individuals with high CYP2C19 but low 3A4 and 2B6 are more active in dearylation than in desulfuration. Similarly, individuals possessing high levels of CYP2B6 and 3A4 have the greatest potential to form the activation product. These differences between individuals suggest that differential sensitivities to CPS may exist in the human population.