Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase.
Exposure of cells to toxic chemical species can result in reduced glutathione (GSH) depletion, generation of free radicals, and/or binding to critical cell determinants. Chemical stress is usually followed by a concerted cellular response aimed at restoring homeostasis, although the precise initial stimulus for the response is unclear. We have focused on one component of this 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 (CCl(4); 1.0 and 0.2 mmol/kg). Biochemical (serum transaminase and hepatic GSH levels) and molecular (c-jun and c-fos messenger RNA [mRNA] levels and activator protein 1 [AP-1] DNA binding activity) parameters were measured, as well as the consequent effects on gamma-GCS levels and activity. All compounds produced GSH depletion, but only the higher doses of APAP and CCl(4) caused liver damage. DEM, APAP, and CCl(4) increased c-jun and c-fos mRNA levels, together with an increase in AP-1 binding; BSO failed to induce AP-1 despite an increase in c-fos. Interestingly, the effects on gamma-GCS varied markedly according to the compound: BSO and DEM increased gamma-GCS enzyme activity, although only DEM, but not BSO, resulted in an increase in gamma-GCS(h) mRNA and protein. In contrast, APAP and CCl(4) both increased gamma-GCS(h) mRNA and protein; however, there was a marked dose-dependent decrease in gamma-GCS activity. These data indicate that the effect of chemical stress on the liver is compound specific and is not merely dependent on depletion of GSH.[1]References
- Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase. Kitteringham, N.R., Powell, H., Clement, Y.N., Dodd, C.C., Tettey, J.N., Pirmohamed, M., Smith, D.A., McLellan, L.I., Kevin Park, B. Hepatology (2000) [Pubmed]
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