Evaluation of the gender differences in 4,4 '-methylenedianiline toxicity,distribution, and effects on biliary parameters

Exposure to 4,4'-diaminodiphenylmethane (DAPM) has been linked to jaundice, toxic hepatitis, cholangitis, and cholestasis. In rodents, DAPM initially injures biliary epithelial cells, and toxicity is greater in female than ma le rats. Our goal was to determine if gender differences in DAPM toxicity w ere due to differences in biliary excretion or covalent binding of DAPM met abolites in the liver. Bile duct-cannulated female and male Sprague-Dawley rats were gavaged with vehicle or with 25 or 50 mg [C-14]DAPM/kg, and bile was collected for 6 h. Serum and bile indicators of hepatobiliary toxicity were assessed, and radioactivity was measured in bile, serum, urine, and li ver. At the 25 mg/kg dose, serum parameters were elevated only in female ra ts, while increases in serum parameters were observed in both genders at th e 50 mg/kg dose. In males rats, biliary constituents altered by DAPM [inorg anic phosphate (P-i), glucose, gamma -glutamyl transpeptidase ( GGT)] showe d time- and dose-dependent responses. In female rats, however, biliary cons tituents showed either minimal dose-response effects ( glucose), were incre ased equivalently at both doses (P-i), or were not altered by DAPM treatmen t (GGT). At the 50 mg/kg dose, liver alkaline phosphatase decreased in fema le but not male rats. Gender also affected the disposition of DAPM metaboli tes. At 25 mg DAPM/kg, male rats had greater amounts of DAPM/ metabolite in bile and liver, while females had greater amounts in serum and urine. Thes e studies thus confirm that (1) DAPM is more toxic in female than male rats , and (2) gender has a significant effect on the disposition and biliary ex cretion of DAPM metabolites.