Evalutaion 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 male rats. Our goal was to determine if gender differences in DAPM toxicity were due to differences in biliary excretion or covalent binding of DAPM metabolites in the liver. Bile duct-cannulated female and male Sprague-Dawley rats were gavaged with vehicle or with 25 or 50 mg [14C]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 liver. At the 25 mg/kg dose, serum parameters were elevated only in female rats, while increases in serum parameters were observed in both genders at the 50 mg/kg dose. In males rats, biliary constituents altered by DAPM [inorganic phosphate (Pi