Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolised by cytochrome P450s (P450s) through either a dearylation reaction to form an inactive metabolite, or through a desulfuration reaction to form an active oxon metabolite, which is a potent cholinesterase inhibitor. This study investigated the rate of desulfuration (activation) and dearylation (detoxification) of methyl parathion and diazinon in human liver microsomes. In addition, recombinant human P450s were used to determine the P 450-specific kinetic parameters (Km and Vmax) for each compound for future use in refining human physiology based pharmacokinetic/pharmacodynamics (PBPK/PD) models of OP exposure. The primary enzymes involved in bioactivation of methyl parathion were CYP2B6, CYP2C19 and CYP1A2, and the bioactivation of diazinon was mediated primarily by CYP1A1, CYP2C19, and CYP2B6. P 450-mediated detoxification of methyl parathion only occurred to a limited extent with CYP1A2 and 3A4, whereas the major enzyme involved in diazinon detoxification was CYP2C19. The OP- and P 450- specific kinetic values will be helpful for future use in refining human PBPK/PD models of OP exposure.
Authors: Ellison, Corie A.; Tian, Yuan; Knaak, James B.; Kostyniak, Paul J.; Olson, James R. ;Full Source: Drug Metabolism & Disposition 2012, 40(1), 1-5 (U.S.A.). ;