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 organ ophosphorus (OP) insecticide, is its biotransformation. CPS can be activate d by cytochrome P450 (CYP) through a desulfuration reaction to form chlorpy rifos-oxon (CPO), a potent anticholinesterase. CPS can also be detoxified b y CYP through a dearylation reaction. Using pooled human liver microsomes ( HLM), a K-mapp of 30.2 muM and V-maxapp of 0.4 nmol/min/mg of protein was o btained for desulfuration, and a K-mapp of 14.2 muM and a V-maxapp of 0.7 n mol/min/mg of protein was obtained for dearylation. These activities are lo wer than those obtained from rat liver microsomes. Gender differences in hu mans were also observed with female HLM possessing greater activity than ma le HLM. Use of human CYP isoforms expressed in human lymphoblastoma cells d emonstrated that CYP1A2, 2B6, 2C9*1, 2C19, and 3A4 are involved in CPS meta bolism. 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, indi viduals with high CYP2C19 but low 3A4 and 2B6 are more active in dearylatio n than in desulfuration. Similarly, individuals possessing high levels of C YP2B6 and 3A4 have the greatest potential to form the activation product. T hese differences between individuals suggest that differential sensitivitie s to CPS may exist in the human population.