Nr. Kitteringham et al., Hepatocellular response to chemical stress in CD-1 mice: Induction of early genes and gamma-glutamylcysteine synthetase, HEPATOLOGY, 32(2), 2000, pp. 321-333
Exposure of cells to toxic chemical species can result in reduced glutathio
ne (GSH) depletion, generation of free radicals, and/or binding to critical
cell determinants. Chemical stress is usually followed by a concerted cell
ular response aimed at restoring homeostasis, although the precise initial
stimulus for the response is unclear. We have focused on one component of t
his stress response, the up-regulation of gamma-glutamylcysteine synthetase
(gamma-GCS) and the preceding molecular events involved in its regulation
in an in vivo mouse model. Male CD-1 mice received buthionine sulphoximine
(BSO; 7.2 mmol/kg), diethyl maleate (DEM; 4.2 mmol/kg), paracetamol (APAP;
3.5 and 1.0 mmol/kg), or carbon tetrachloride (CCl4; 1.0 and 0.2 mmol/kg).
Biochemical (serum transaminase and hepatic GSH levels) and molecular (c-ju
n and c-fos messenger RNA [mRNA] levels and activator protein 1 [AP-1] DNA
binding activity) parameters were measured, as well as the consequent effec
ts on gamma-GCS levels and activity. All compounds produced GSH depletion,
but only the higher doses of APAP and CCl4 caused liver damage. DEM, APAP,
and CCl4 increased c-jun and c-fos mRNA levels, together with an increase i
n AP-1 binding; BSO failed to induce AP-1 despite an increase in c-fos. Int
erestingly, the effects on gamma-GCS varied markedly according to the compo
und: BSO and DEM increased gamma-GCS enzyme activity, although only DEM, bu
t not BSO, resulted in an increase in gamma-GCS(h) mRNA and protein. In con
trast, APAP and CCl4 both increased gamma-GCS(h) mRNR and protein; however,
there was a marked dose-dependent decrease in gamma-GCS activity. These da
ta indicate that the effect of chemical stress on the liver is compound spe
cific and is not merely dependent on depletion of GSH.