Metabolism of trichloroethylene.

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 ,B Iyase 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.

Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice

“…The kidneys are the primary target of TCE, and nephrotoxicity is linked to metabolism of TCE via the glutathione conjugation pathway (Caldwell and Keshava, 2006;Lock and Reed, 2006;Lash et al, 2000aLash et al, , 2000b. Once glutathione conjugate is formed, it is further metabolized to the cysteine conjugate DCVC, which is subsequently activated through α,β-elimination by the action of the cysteine conjugate β-lyase (Tateishi et al, 1987).…”

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

“…Evidence of the continued interest in the toxicity and human health risk of TRI is highlighted by a series of recent reviews that summarize current state of knowledge and uncertainties [3][4][5][6]. Evaluation of the risk for humans potentially exposed to TRI in either the workplace or due to environmental contamination is complicated by the existence of multiple metabolic pathways, multiple target organs, poor or incomplete exposure data for many epidemiology studies, and sex-and species-dependent differences in sensitivity to toxic effects [3,6,7].…”

“…The kidneys are one target organ for TRI, and toxicity and carcinogenicity are linked to metabolism of TRI by the glutathione (GSH) conjugation pathway [3,5,7,8]. Once the GSH conjugate is formed, it is further metabolized to the cysteine conjugate S-(1,2-dichlorovinyl)-L-cysteine (DCVC), which is the penultimate nephrotoxic species and has been the focus of most of the mechanistic studies of TRI-induced nephrotoxicity.…”

“…Despite these advances in our understanding of mechanisms of action of DCVC in renal injury, extrapolation of these findings to human kidney involves uncertainties because of species differences in metabolism, transport, and overall susceptibility to injury [3][4][5]7,8]. To solve the problems inherent in interspecies extrapolation, one approach has been to conduct studies in freshly isolated and primary cultures of human PT (hPT) cells.…”

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

“…It is well established that TCE undergoes metabolism by hepatic cytochrome P450 in experimental animals and man to produce chloral hydrate (CH) which is then further metabolised to TCE-OH and TCA (Davidson and Beliles, 1991;Elfarra et al, 1998;Lash et al, 2000;Bloemen et al, 2001;Lock and Reed, 2006). The target organs for toxicity and carcinogenicity following exposure of rats or mice to TCE are the liver, kidney and lung (Bull, 2000;Green, 2000;Lock and Reed, 2006).…”