Role of intrarenal biotransformation in chloroform-induced nephrotoxicity in rats

Abstract

Various ketonic agents potentiate the hepatic and renal toxicity of halogenated solvents in mice and rats. Characteristics of CHCl 3 nephrotoxicity and of 2-hexanone potentiation were evaluated in adult male Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone (10 mmol/kg, po) 18 hr prior to CHCl 3 exposure. In contrast to the liver, little metabolism of 14CHCl 3 by renal cortical microsomes from vehicle- or 2-hexanone-pretreated rats was detected. However, CHCl 3 produced a concentration-related dysfunction when added to renal cortical slices from Fischer 344 or Sprague-Dawley rats. The degree of CHCl 3 toxicity in vitro was not altered when renal cortical slices were preincubated with CHCl 3 (8.5 μl) under an atmosphere of carbon monoxide. In renal cortical slices, deuterated-CHCl 3 was less toxic than CHCl 3. Although 2-hexanone pretreatment increased renal slice metabolism of 14CHCl 3 twofold, this increase was not associated with an increase in nephrotoxicity after direct exposure of slices to CHCl 3 (0 to 10 μl) in vitro. CHCl 3 (0.5 ml/kg, ip) did not alter renal cortical glutathione concentrations in vehicle or 2-hexanone pretreated rats. The association of 14CHCl 3-derived radiolabel was increased over control by 2-hexanone pretreatment in protein, lipid, and acid soluble fractions from the renal cortex by approximately two-, two-, and fivefold, respectively. In conclusion, renal cytochrome P-450 did not appear to mediate CHCl 3 metabolism and nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone appeared to potentiate nephrotoxicity by a mechanism different than that observed in rat liver.