Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Abstract

Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute-chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-pM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPARa) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPARa that are observed in rodents. This may be attributed to lower levels of expressed PPARax in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis. Key words: chloral hydrate, dichloroacetate, liver tumors, mode of action, trichloroacetate, trichloroethylene. -Environ Health Perspect 108(suppl 2):241-259 (2000). http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-2/24 1-259bull/abstract. html

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

“…While CH was the primary P450-derived metabolite recovered in liver, particularly at early time points, TCA was the predominant P450-derived metabolite recovered in kidney homogenates. This is an interesting and unexpected finding because TCA has been associated with toxic and carcinogenic effects of TRI in liver (Bull, 2000) and no effects on renal function have been ascribed to this metabolite (Lash et al, 1995(Lash et al, , 2000a(Lash et al, , 2000b). Thus, while rat kidney can catalyze formation of P450-dependent metabolites of TRI (Cummings et al, 2001), the implications of this activity for TRI-induced toxicity for humans remain unclear.…”

Probabilistic methods for addressing uncertainty and variability in biological models: application to a toxicokinetic model

“…This highly fat-soluble compound is rapidly absorbed into the bloodstream, and has been shown to accumulate in the adipose (fat) tissue of humans and animals [1,2]. Known and suspected toxic effects of TCE and its metabolites in laboratory animals and/or humans include acute effects such as dizziness, drowsiness, headaches and fatigue, as well as chronic effects such as developmental defects and lung, kidney and liver tumors [3][4][5][6][7][8][9][10].…”

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

“…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). TCE has been reported to undergo metabolism to CH in rat liver (see references above) and rat kidney (Cummings et al, 2001) primarily by cytochrome P450 2E1, although other cytochromes P450 such as 2B1 and 2C11 can also convert TCE to CH.…”