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Lawrence H. Lash,¹ Jeffrey W. Fisher,² John C. Lipscomb,³ and Jean C. Parker⁴

¹Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan USA; ²Toxicology Division, Armstrong Laboratory, Wright-Patterson AFB, Ohio USA; ³National Center for Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, Ohio USA; ⁴National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC USA

Abstract

A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex- and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450) -dependent oxidation and conjugation with glutathione (GSH) . Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ß-lyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from in vitro studies, can be extrapolated to humans for risk assessment. Key words: conjugate beta-lyase, cysteine glutathione, cytochrome P450, glutathione S-transferases, metabolism, sex dependence, species dependence, tissue dependence, trichloroethylene. -- Environ Health Perspect 108(suppl 2) :177-200 (2000) .

http://ehpnet1.niehs.nih.gov/docs/2000/suppl-2/177-200lash/abstract.html