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ToxSci Advance Access published online on April 21, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh118
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received November 12, 2003
Accepted February 15, 2004

Biotransformation and Toxicokinetics

Biotransformation of Methyl Parathion by Glutathione S-Transferases

Erika L. Abel 1, Theo K. Bammler 1, David L. Eaton 1*

1 Department of Environmental and Occupational Health Sciences and Center for Ecogenetics & Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, Washington 98105

* To whom correspondence should be addressed. E-mail: deaton{at}u.washington.edu.


  Abstract

The organo(thio)phosphate esters are one of the most widely used classes of insecticides. Worldwide, organophosphate insecticides (OPs) result in numerous poisonings each year. In insects, glutathione S-transferases (GSTs) play an important role in OP resistance; limited data suggest that GST-mediated O-dealkylation occurs in humans as well. To characterize the capacity of mammalian GSTs to detoxify OPs, we investigated mammalian GST biotransformation of the widely used OP, methyl parathion (MeP). Cytosolic fractions isolated from rat, mouse and 10 individual adult human livers biotransformed 300 µM MeP at rates of 2.36, 1.76 and 0.70 (mean rate) nmol desmethyl parathion/min/mg respectively. Our study focused on human GSTs; in particular we investigated hGSTs M1-1 and T1-1 since deletion polymorphisms occur commonly in these genes. However, we found no correlation between hGSTM1/T1 genotypes and MeP O-dealkylation activities of the 10 human liver cytosolic samples. We also measured MeP O-dealkylation activities of several purified recombinant GSTs belonging to the alpha (human GSTs A1-1 and A2-2, mouse GSTA3-3, rat GSTA5-5), mu (human GSTs M1a-1a, M2-2, M3-3, M4-4), pi (human GSTP1-1, mouse GSTs P1-1, P2-2) and theta (human GSTT1-1) classes. At 1 mM glutathione and 300 µM MeP concentrations, hGSTT1-1 and hGSTA1-1 exhibited the highest O-dealkylation activities: 545.8 and 65.0 nmol/min/mg respectively. When expression level and enzymatic activity are considered, we estimate that hGSTA1-1 is responsible for the majority of MeP O-dealkylation in human hepatic cytosol. In target organs such as brain and skeletal muscle where hGSTT1-1 is expressed, hGSTT1-1 mediated biotransformation of MeP may be important.


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