Acute acetaminophen toxicity in transgenic mice with elevated hepatic glutathione

Previous studies demonstrated that elevation of hepatic glutathione (GSH) c oncentrations protect against acetaminophen (APAP) hepatotoxicity in mice. Employing transgenic mice overexpressing glutathione synthetase, this study was conducted to determine if sustained elevation of hepatic GSH concentra tions could ameliorate or prevent APAP toxicity. International Cancer Resea rch transgenic mouse males and matched (ie same strain, sex, and age) contr ol nontransgenic mice were pretreated ip with GSH synthetase substrate gamm a-glutamylcysteinyl ethyl ester (gamma-GCE) or with saline. After a 16-h fa st. mice received a single dose of 500 mg APAP/kg bw in saline ip and were sacrificed 4 h later. Other mice similarly pretreated were killed without A PAP challenge. The elevated GSH concentrations in transgenic mice livers di d not lessen APAP hepatotoxicity. Instead higher degrees of hepatotoxicity and nephrotoxicity were observed in transgenic mice than in controls as ind icated by higher serum alanine aminotransferase activity and more severe hi stopathological lesions in transgenic mice livers and kidneys. Pretreatment with gamma-GCE did not affect either initial or post-APAP treatment tissue GSH concentrations or observed degrees of toxicity. Detection of a higher level of serum APAP in transgenic mice and the histopathological lesions fo und in transgenic mice kidneys together with no observable nephrotoxicity i n control mice indicated early kidney damage in transgenic mice. Our findin gs suggest that high levels of GSH-APAP conjugates resulting from increased GSH concentrations in the livers of transgenic mice caused rapid kidney da mage. Compromised excretory ability may have caused retention of APAP, whic h, in effect, elicited higher hepatotoxicity than that observed in nontrans genic mice.