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

Chloroform (CHCl3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl3 administration (250 microliter/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 CHCl3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl3 even when the dose was increased to 1000 microliter/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl3 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 CHCl3 administration. The rapid response of the kidney to CHCl3 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 CHCl3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl3 nephrotoxicity.