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),
glucose,
gamma-glutamyl transpeptidase (GGT)] showed time- and dose-dependent responses. In female rats, however, biliary constituents showed either minimal dose-response effects (
glucose), were increased equivalently at both doses (Pi), or were not altered by
DAPM treatment (GGT). At the 50 mg/kg dose, liver
alkaline phosphatase decreased in female but not male rats. Gender also affected the disposition of
DAPM metabolites. 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. These 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 excretion of
DAPM metabolites.