Dose-dependent liver regeneration in chloroform, trichloroethylene and allyl alcohol ternary mixture hepatotoxicity in rats

Abstract

The present study was designed to examine the hypothesis that liver tissue repair induced after exposure to chloroform (CF) + trichloroethylene (TCE) + allyl alcohol (AA) ternary mixture (TM) is dose-dependent similar to that elicited by exposure to these compounds individually. Male Sprague Dawley (S-D) rats (250-300 g) were administered with fivefold dose range of CF (74-370 mg/kg, ip), and TCE (250-1250 mg/kg, ip) in corn oil and sevenfold dose range of AA (5-35 mg/kg, ip) in distilled water. Liver injury was assessed by plasma alanine amino transferase (ALT) activity and liver tissue repair was measured by (3) H-thymidine incorporation into hepatonuclear DNA. Blood and liver levels of parent compounds and two major metabolites of TCE [trichloroacetic acid (TCA) and trichloroethanol (TCOH)] were quantified by gas chromatography. Blood and liver CF and AA levels after TM were similar to CF alone or AA alone, respectively. However, the TCE levels in blood and liver were substantially decreased after TM in a dose-dependent fashion compared to TCE alone. Decreased plasma and liver TCE levels were consistent with decreased production of metabolites and elevated urinary excretion of TCE. The antagonistic interaction resulted in lower liver injury than the summation of injury caused by the individual components at all three-dose levels. On the other hand, tissue repair showed a dose-response leading to regression of injury. Although the liver injury was lower and progression was contained by timely tissue repair, 50% mortality occurred only with the high dose combination, which is several fold higher than environmental levels. The mortality could be due to the central nervous system toxicity. These findings suggest that exposure to TM results in lower initial liver injury owing to higher elimination of TCE, and the compensatory liver tissue repair stimulated in a dose-dependent manner mitigates progression of injury after exposure to TM.

Radio-protective response on the environmental pollutant induced oxidative stress

“…According to Anand and his colleagues, Pratt and Kaplan and Lawrence and his colleagues, this elevation may be due to the generation of free radical induced damage in liver function [36][37][38]. Moffalt and Denizeau, found that higher dose of Zn accompanied with higher serum activities of transaminease and alkaline phosphatase, which is in agreement with the present study [39].…”

Computational Toxicology Methods in Public Health Practice

“…Inhalation studies in rats show that at high doses, trichloroethylene can compete with 1,1-dichloroethylene for CYP2E1 active sites, resulting in a less than additive metabolic interaction (Andersen et al 1987b;El-Masri et al 1996a). Similarly, a study in rats using simultaneous acute intraperitoneal administration demonstrated less than additive liver toxicity of chloroform and trichloroethylene in combination compared to either of the chemicals administered alone (Anand et al 2005). These results are consistent with mechanistic understanding that predicts competitive inhibition at the CYP2E1 level of metabolic pathways of these chemicals at high-dose exposures.…”