Abstract

Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolized 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 P450-specific kinetic parameters (K_m and V_max) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. The primary enzymes involved in bioactivation of methyl parathion were CYP2B6 (K_m = 1.25 μM; V_max = 9.78 nmol · min⁻¹ · nmol P450⁻¹), CYP2C19 (K_m = 1.03 μM; V_max = 4.67 nmol · min⁻¹ · nmol P450⁻¹), and CYP1A2 (K_m = 1.96 μM; V_max = 5.14 nmol · min⁻¹ · nmol P450⁻¹), and the bioactivation of diazinon was mediated primarily by CYP1A1 (K_m = 3.05 μM; V_max = 2.35 nmol · min⁻¹ · nmol P450⁻¹), CYP2C19 (K_m = 7.74 μM; V_max = 4.14 nmol · min⁻¹ · nmol P450⁻¹), and CYP2B6 (K_m = 14.83 μM; V_max = 5.44 nmol · min⁻¹ · nmol P450⁻¹). P450-mediated detoxification of methyl parathion only occurred to a limited extent with CYP1A2 (K_m = 16.8 μM; V_max = 1.38 nmol · min⁻¹ · nmol P450⁻¹) and 3A4 (K_m = 104 μM; V_max = 5.15 nmol · min⁻¹ · nmol P450⁻¹), whereas the major enzyme involved in diazinon detoxification was CYP2C19 (K_m = 5.04 μM; V_max = 5.58 nmol · min⁻¹ · nmol P450⁻¹). The OP- and P450-specific kinetic values will be helpful for future use in refining human PBPK/PD models of OP exposure.