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First published on November 1, 2006; DOI: 10.1124/dmd.106.012427

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Received for publication August 9, 2006.
Revised October 24, 2006.
Accepted for publication October 25, 2006.

Human Hepatic Cytochrome P450 -Specific Metabolism of Parathion and Chlorpyrifos

Robert J Foxenberg 1, Barbara P McGarrigle 1, James B Knaak 1, Paul J Kostyniak 1, James R Olson 1*

1 University at Buffalo

* Address correspondence to: E-mail: jolson{at}buffalo.edu

Abstract

Organophosphorous pesticides (OPs) remain a potential concern to human health due to their continuing world-wide use. Thiophosphorous OPs, once bio-activated by cytochrome P450s (CYPs), 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 CYPs were utilized to quantify for the first time the CYP -specific kinetic variables (Km and Vmax) for each compound for future use in refining human PBPK/PD models of OP exposure. CYPs 1A2, 2B6, 2C9, 2C19, 3A4, 3A5, and 3A7 were found to be active to a widely varying degree in parathion metabolism while 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 being the primary enzymes which 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, 12544 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, 13128 pmol/min/nmol for formation of p-nitrophenol and 3,4,5-tricholorpyrindinol respectively. CYP -specific kinetic parameters for OP metabolism will be utilized with age -dependent hepatic CYP content to enhance PBPK/PD models so that OP exposures can be modeled to protect human health in different age groups.


Key words: bioactivation, cytochrome P450, environmental toxicology, enzyme kinetics, human CYP enzymes, human pharmacokinetics, insecticides, pharmacokinetic/pharmacodynamic modeling, toxicokinetics




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