Modes of action of trichloroethylene for kidney tumorigenesis.

Abstract

This article focuses on the various models for kidney toxicity due to trichloroethylene (TCE) and its glutathione-dependent metabolites, in particular S-(1,2-dichlorovinyl)-l-cysteine. Areas of controversy regarding the relative importance of metabolic pathways, species differences in toxic responses, rates of generation of reactive metabolites, and dose-dependent phenomena are highlighted. The first section briefly reviews information on the incidence and risk factors of kidney cancer in the general U.S. population. Epidemiological data on incidence of kidney cancer in male workers exposed occupationally to TCE are also summarized. This is contrasted with cancer bioassay data from laboratory animals, that highlights sex and species differences and, consequently, the difficulties in making risk assessments for humans based on animal data. The major section of the article considers proposed modes of action for TCE or its metabolites in kidney, including peroxisome proliferation, alpha(2u)-globulin nephropathy, genotoxicity, and acute and chronic toxicity mechanisms. The latter comprise oxidative stress, alterations in calcium ion homeostasis, mitochondrial dysfunction, protein alkylation, cellular repair processes, and alterations in gene expression and cell proliferation. Finally, the status of risk assessment for TCE based on the kidneys as a target organ and remaining questions and research needs are discussed.

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

“…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.…”

Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

“…By contrast, the GST pathway, which yields S- (1,2-dichlorovinyl) (NAcDCVC) as major metabolites, only becomes quantitatively significant in overall metabolism of TRI at relatively high substrate concentrations. This fact may be deceptive, however, because further metabolism of DCVC by either the cysteine conjugate β-lyase (β-lyase) or flavin-containing monooxygenase (FMO) produces highly reactive chemical species that may bind to DNA, protein or lipid and produce nephrotoxicity and/or nephrocarcinogenicity (Lash et al, 2000b). Much smaller amounts of these reactive species may be required to elicit a toxic response as compared to required amounts of stable end-products produced by the P450 pathway (Lash et al, 1988).…”