Mechanism of chloroform nephrotoxicity. II. In vitro evidence for renal metabolism of chloroform in mice.

Preincubation of renal cortical slices with chloroform (CHCl3) from male, but not female, mice resulted in a subsequent decrease of the ability of the slices to accumulate the organic ions, p-aminohippurate (PAH) and tetraethylammonium (TEA). These sex-related differences, the time required for manifestation of this effect (60 to 90 min), and the concentration dependency (0 to 50 mumol, 0 to 4 microliter CHCl3) were similar to in vivo observations on CHCl3 nephrotoxicity in mice. Furthermore, an equimolar concentration of deuterated CHCl3 (CDCl3) in vitro was less effective than CHCl3 in decreasing PAH and TEA accumulation in male renal cortical slices. The effects of CHCl3 on PAH and TEA accumulation could be diminished or blocked by preincubation with CHCl3 in the presence of carbon monoxide or at 0 degrees C, respectively. The nephrotoxicity of CHCl3 in vitro was increased in renal cortical slices from male mice pretreated with diethyl maleate. Thus, this in vitro model with mouse renal cortical slices and the sex-related differences in CHCl3 nephrotoxicity suggests that the kidney may metabolize CHCl3 in situ to a nephrotoxic metabolite.