PT  - JOURNAL ARTICLE
AU  - Robert J. Foxenberg
AU  - Barbara P. McGarrigle
AU  - James B. Knaak
AU  - Paul J. Kostyniak
AU  - James R. Olson
TI  - Human Hepatic Cytochrome P450-Specific Metabolism of Parathion and Chlorpyrifos
AID  - 10.1124/dmd.106.012427
DP  - 2007 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 189--193
VI  - 35
IP  - 2
4099  - http://dmd.aspetjournals.org/content/35/2/189.short
4100  - http://dmd.aspetjournals.org/content/35/2/189.full
SO  - Drug Metab Dispos2007 Feb 01; 35
AB  - Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing worldwide use. Thiophosphorus OPs, once bioactivated by cytochromes P450 (P450s), form oxon metabolites, which are potent acetylcholinesterase inhibitors. This study investigated the rate of desulfation (activation) and dearylation (detoxification) of parathion and chlorpyrifos in human liver microsomes. In addition, recombinant human P450s were used to quantify, for the first time, the P450-specific kinetic variables (Km and Vmax) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. CYP1A2, 2B6, 2C9, 2C19, 3A4, 3A5, and 3A7 were found to be active to a widely varying degree in parathion metabolism, whereas all, with the exception of CYP2C9, were also found to be active in chlorpyrifos metabolism. CYP2B6 and CYP2C19 demonstrated low Km and high Vmax values for the metabolism of both model compounds, which supports their role as the primary enzymes that regulate metabolism at low-level human exposures to OPs. With Km and Vmax values of 0.61 μM, 4827 pmol/min/nmol P450 and 0.81 μM, 12,544 pmol/min/nmol for formation of paraoxon and chlorpyrifos-oxon, respectively, CYP2B6 favored the desulfation reaction. CYP2C19 activity favored dearylation with Km and Vmax values of 0.60 μM, 2338 pmol/min/nmol P450 and 1.63 μM, 13,128 pmol/min/nmol for formation of p-nitrophenol and 3,4,5-tricholorpyrindinol, respectively. P450-specific kinetic parameters for OP metabolism will be used with age-dependent hepatic P450 content to enhance PBPK/PD models so that OP exposures can be modeled to protect human health in different age groups. The American Society for Pharmacology and Experimental Therapeutics