Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Abstract

Metabolism is critical for the mutagenicity, carcinogenicity, and other adverse health effects of trichloroethylene (TCE). Despite the relatively small size and simple chemical structure of TCE, its metabolism is quite complex, yielding multiple intermediates and end-products. Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways. We describe the catalytic enzymes, their regulation and tissue localization, as well as the evidence for transport and inter-organ processing of metabolites. We address the chemical reactivity of TCE metabolites, highlighting data on mutagenicity of these end-products. Identification in urine of key metabolites, particularly trichloroacetate (TCA), dichloroacetate (DCA), trichloroethanol and its glucuronide (TCOH and TCOG), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), in exposed humans and other species (mostly rats and mice) demonstrates function of the two metabolic pathways in vivo. The CYP pathway primarily yields chemically stable end-products. However, the GST pathway conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) is further processed to multiple highly reactive species that are known to be mutagenic, especially in kidney where in situ metabolism occurs. TCE metabolism is highly variable across sexes, species, tissues and individuals. Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity.

Comparative Analysis of the Relationship Between Trichloroethylene Metabolism and Tissue-Specific Toxicity Among Inbred Mouse Strains: Liver Effects

“…Some understanding of the human population variability in toxicokinetics of TCE is available based on the limited data from clinical studies and Bayesian modeling (Chiu et al 2009). The metabolism of TCE across species ( e.g ., rodents and humans) is qualitatively similar (Lash et al 2014), and thus inter-species and –individual variability in TCE toxicity is likely due to the variability in TCE metabolism (Chiu et al 2013; Green 1990). TCE toxicity is also dose-dependent, which suggests the link between toxicokinetics and toxicodynamics (Chiu et al 2013).…”

“…TCE is metabolized through both cytochrome P450-dependent oxidation and glutathione conjugation to form a number of toxic species (Lash et al 2014). Metabolites of the oxidative pathway, trichloroacetic (TCA) and dichloroacetic (DCA) acids, are widely considered to be primary mediators of the toxicity and carcinogenicity of TCE in the liver via peroxisome proliferator-activated receptor (PPARα) activation.…”

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

“…Metabolism of TCE and PCE can result in both intoxication and detoxication. Hepatic cytochrome P450 2E1 (CYP2E1) is proposed to be the main contributor to oxidative metabolism of TCE, although other P450s are also involved Lash et al, 2014). Oxidative metabolism of PCE has also been attributed primarily to CYP2E1 activity owing to its structural similarity to other CYP2E1 substrates , although this is yet to be confirmed experimentally.…”

“…For TCE, major metabolites are TCOH and TCA; for PCE, TCA is the major metabolite. This is based on human data (Bernauer et al, 1996;Volkel and Dekant, 1998;Lash et al, 1999) and in vivo and in vitro experimental rodent data Bradford et al, 2011;Lash et al, 2014;Yoo et al, 2015a,b). In both humans and experimental animals, it is evident that exposure to TCE or PCE results in larger urinary levels of oxidative TCE/PCE metabolites compared with mercapturic acids derived from the GSH conjugation pathway.…”

“…PCE-associated chronic nephropathy, including karyomegaly, occurs in rats (National Toxicology Program, 1977, 1986) of both sexes after chronic exposure. Renal injury associated with TCE or PCE exposure is probably mediated through GSH5conjugative metabolites (i.e., DCVG/TCVG and DCVC/TCVC) Lash et al, 2014;Rusyn et al, 2014).…”