Hepatocellular response to chemical stress in CD-1 mice: Induction of early genes andγ-glutamylcysteine synthetase
| Autor: | Munir Pirmohamed, B. Kevin Park, Helen Powell, Dennis A. Smith, Y Clement, Charlotte C. Dodd, Lesley I. McLellan, Neil R. Kitteringham, Justice N. Tettey |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Glutamate-Cysteine Ligase Biology Mice chemistry.chemical_compound Genes jun In vivo medicine Animals Buthionine Sulfoximine Carbon Tetrachloride Acetaminophen chemistry.chemical_classification Messenger RNA Hepatology Reverse Transcriptase Polymerase Chain Reaction Maleates Genes fos Glutathione Molecular biology Enzyme assay Transcription Factor AP-1 medicine.anatomical_structure Enzyme Gene Expression Regulation Liver Biochemistry chemistry Hepatocyte Carbon tetrachloride biology.protein Homeostasis |
| Zdroj: | Hepatology. 32:321-333 |
| ISSN: | 1527-3350 0270-9139 |
| DOI: | 10.1053/jhep.2000.9602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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