Hepatotoxicity and metabolism of acetaminophen in male and female rats

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Abstract
The role of metabolic and pharmacokinetic factors in the lower susceptibility of female rats compared to male rats to xenobiotics metabolized by the cytochrome P-450-dependent mixed-function oxidase (MFO) system was assessed. Adult intact male and female Sprague-Dawley rats were administered labeled acetaminophen [APAP] (1 g/kg body wt + 5 .mu.Ci [3H]actaminophen) after an overnight fast. They were bled and killed at 0.5, 1, 2, 3, 6, 12, 24 and 36 h after drug administration. The percentage of [3H]APAP radioactivity remaining in blood, liver, GI [gastrointestinal] tract and excreted in the urine was determined at all time intervals. Plasma prothrombin time and serum transaminases were determined as indices of hepatotoxicity. Hepatic GSH [glutathoine] and glycogen were assayed. Total urinary APAP and its metabolites and the molar percent of various metabolites excreted during the 1st 6 h were determined. Castrated male and ovariectomized female rats and their respective controls were aslso given APAP and were killed 24 h later to determine hepatotoxicity. The extent of hepatic damage in the intact male rats was greater and appeared sooner. Hepatic GSH and glycogen were depleted earlier in female rats. The percent of the administered dose excreted in the urine during the first 6 h was 17.5 for the male rat vs. 24.5 for the female rat. While the APAP glucuronide conjugate concentration was significantly higher, the APAP sulfate conjugate concentration was lower in the female rat. Although peak radioactivity in serum was reached by 30 min in both sexes, suggesting quick intestinal absorption, it was significantly higher in female rats and was associated with decreased intestinal and hepatic levels and increased urinary excretion. While castration of male rats decreased susceptibility to hepatotoxicity, ovariectomy of female rats tended to increase susceptibility to hepatotoxicity. Aside from the reported sex differences in the cytochrome P-450-dependent MFO enzymes, there were significant differences in GSH utilization. There were also significant changes in glucuronidation and sulfation pathways, and in the pharmacokinetics of APAP which tended to protect female rats against APAP hepatotoxicity.