Previous studies demonstrated that elevation of hepatic
glutathione (GSH) concentrations 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 concentrations could ameliorate or prevent
APAP toxicity. International
Cancer Research transgenic mouse males and matched (ie same strain, sex, and age) control nontransgenic mice were pretreated ip with GSH
synthetase substrate gamma-glutamylcysteinyl ethyl
ester (
gamma-GCE) or with saline. After a 16-h fast, 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
APAP challenge. The elevated GSH concentrations in transgenic mice livers did not lessen
APAP hepatotoxicity. Instead higher degrees of hepatotoxicity and nephrotoxicity were observed in transgenic mice than in controls as indicated by higher serum
alanine aminotransferase activity and more severe histopathological 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 found in transgenic mice kidneys together with no observable nephrotoxicity in control mice indicated early kidney damage in transgenic mice. Our findings suggest that high levels of GSH-
APAP conjugates resulting from increased GSH concentrations in the livers of transgenic mice caused rapid kidney damage. Compromised excretory ability may have caused retention of
APAP, which, in effect, elicited higher hepatotoxicity than that observed in nontransgenic mice.