The relative importance of glutathione and metallothionein on protection of hepatotoxicity of menadione in rats.
The effects of induction of metallothionein (MT) on the toxicity of menadione were investigated in rat liver slices. The protective role of hepatic glutathione (GSH) was also studied and compared to that of MT. A 3-h incubation of rat liver slices with menadione (100-300 microM) containing medium (37 degrees C, pH 7.4, 95%O2:5%CO2) resulted in cellular toxicity, as shown by changes in cytosolic K, Ca and GSH concentrations and lactate dehydrogenase (LDH) leakage. A dose-dependent decrease in cytosolic K and GSH was observed concomitant with an increase in cytosolic Ca and LDH leakage after incubation with menadione. Pretreatment of rats with zinc sulphate (ZnSO4) (30 mg/kg body wt.) increased MT levels in liver slices and suppressed the toxicity of menadione. Intracellular GSH concentrations in liver slices were either depleted or increased by injection of rats with buthionine sulfoximine (BSO), (4 mmol/kg body wt.) and N-acetyl-L-cysteine (NAC) (1.6 g/kg body wt.), respectively. Intracellular GSH was found to be crucial in protection against menadione toxicity. Menadione toxicity was increased when the rats were injected with sodium phenobarbital (PB) (4 x 80 mg/kg body wt.). Pretreatment with Zn provided partial protection against menadione toxicity in liver slices from both BSO- and PB-injected rats. These findings suggest that induction of MT synthesis does protect against quinone-induced toxicity, but the role may be secondary to that of GSH. The mechanisms by which MT protect against menadione toxicity are still unclear but may involve protection of both redox cycling and sulphydryl arylation.
Chan
H M
HM
Department of Pathology, University of Western Ontario, London, Canada.
Tabarrok
R
R
Tamura
Y
Y
Cherian
M G
MG
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D002118:Calcium / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000502:physiology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000502:physiology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000494:pharmacology; D014812:Vitamin K / Q000633:toxicity*; D015032:Zinc / Q000494:pharmacology; D019287:Zinc Sulfate
D013431:Sulfates; D014812:Vitamin K; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D019287:Zinc Sulfate; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D015032:Zinc; D011188:Potassium; D002118:Calcium; D000111:Acetylcysteine; D010634:Phenobarbital