1,1-Dichloroethylene hepatotoxicity: Proposed mechanism of action and distribution and binding of 14 C radioactivity following inhalation exposure in rats

Abstract

1,1-Dichloroethylene is reported to produce renal tumors in male mice. It is an hepatotoxin in fasted rats after inhalation. We found that trichloropropane epoxide, an inhibitor of epoxide hydrase, enhances hepatic injury as measured by serum sorbitol dehydrogenase elevation. A significant elevation of hepatic citric acid concentration was seen in fasted but not fed rats. We hypothesized that mitochondrial injury was associated with inhibition of the tricarboxylic acid cycle and postulated that monochloroacetic acid was a toxic metabolite of 1,1-DCE. Fluoroacetic acid and chloroacetic acid were similar in their ability to inhibit oxygen uptake when pyruvic and malic acids were substrates in isolated mitochondria supplemented with adenosine diphosphate. In experiments where 1,1-DCE metabolism was estimated, no difference between the rate of uptake in a 2-hr period was detected between fed and fasted animals. Urinary output of radioactivity at 26 hr for fed and fasted rats was similar. Water-soluble (i.e. TCA-soluble) 1,1-DCE metabolites were found in tissues of fasted rats in excess of that seen in fed rats. The kidney had the largest concentration of total metabolites. Tissue-bound, or TCA-insoluble, radioactivity was associated with the mitrochondrial and microsomal fraction of fasted rats in excess of that seen in fed rats. The disappearance of TCA-insoluble radioactivity from the mitochondrial and microsomal fractions was comparable in rate between fed and fasted rats respectively. These results suggest that 1,1-DCE is metabolized quite rapidly in the organism to TCA-soluble components which are excreted by the kidneys. Metabolites of 1,1-DCE may enter the metabolic pool, since a reasonably short turnover of (14)C-labeled, bound material was observed. The metabolite of 1,1-DCE appears to inhibit the mitochondria so that citric acid accumulates. This may occur by a process of lethal synthesis.