Chloroform toxicity in the mouse: Role of genetic factors and steroids

DBA/2J male mice are more sensitive to the 10-day lethal effect of chloroform (CHCl₃) than are C57BL/6J males, whereas B6D2F₁/J mice are intermediate. This relative order of sensitivity is preserved following sublethal doses of CHCl₃ in regard to radiolabel accumulation into subcellular biochemical fractions and renal, but not hepatic, dysfunction. Kidneys from mice of all three genotypes are able to repair tubular damage from CHCl₃. Thus genotypic differences in response to the toxic effects of CHCl₃ are manifestations of differences in renal, rather than hepatic, responses or the ability to repair renal damage. Prior to toxic exposure to chloroform covalent binding of ¹⁴CHCl₃ to renal microsomes was greater in DBA than in C57BL mice. Phenobarbital pretreatment enhanced covalent binding by renal microsomes from DBA, but not from C57BL mice. Testosterone sensitizes kidneys of both male and female DBA/2J and C57BL/6J mice in a dose-dependent fashion to the toxic effects of CHCl₃. The androgenic progestin, medroxyprogesterone acetate, invokes similar responses. These effects are probably mediated in the kidneys by the androgen receptor. Progesterone and hydrocortisone sensitize kidneys to CHCl₃ in DBA/2J males, but not in females, nor in C57BL/6J mice of either sex.