Strain and sex differences in chloroform-induced nephrotoxicity. Different rates of metabolism of chloroform to phosgene by the mouse kidney.

It has been known for many years that there are species, strain, and sex differences in the incidence and severity of the nephrotoxicity caused by chloroform. However, the molecular basis for these differences has not been clearly understood. In this investigation, we have found that sensitivity to CHCl3 correlates with the capacity of the kidney to metabolize CHCl3 to the toxic metabolite phosgene (COCl2). For example, kidney homogenates of sensitive male DBA/2J mice metabolized CHCl3 to COCl2 more rapidly than did the less sensitive C57BL/6J mice. Similarly, kidney homogenates from male mice, which are sensitive to CHCl3-induced nephrotoxicity, metabolized CHCl3 to COCl2 at nearly an order of magnitude more rapidly than did those from female mice. Treatment of female mice with testosterone, however, reversed this trend. Cytochrome P-450 in the microsomal and mitochondrial fraction of the kidney appeared to catalyze the metabolism of CHCl3 to COCl2.