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 μmol, 0 to 4 μl 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°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.