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.