Mechanism of chloroform nephrotoxicity: I. Time course of chloroform toxicity in male and female mice

Abstract

Chloroform (CHCl 3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl 3 administration (250 μl/kg, sc) as decreased ability of renal cortical slices to accumulate p-aminohippurate (PAH) and tetraethylammonium (TEA). The decrease was preceded and paralleled by a reduction of renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration. Histologic alterations were not observed until NPSH concentrations and PAH and TEA accumulation had reached the nadir, 5 hr after CHCl 3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl 3 even when the dose was increased to 1000 μl/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl 3 injection. The extent of hepatotoxicity was similar in male and female mice and decreases of hepatic NPSH concentrations also were detected by 1.5 hr after CHCl 3 administration. The rapid response of the kidney to CHCl 3 toxicity in male mice and the similarity of liver toxicity in both sexes suggests that nephrotoxicity occurs independently of hepatotoxicity. Furthermore, the ability to detect these early changes in vivo following CHCl 3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl 3 nephrotoxicity.