VANADATE-INDUCED TOXICITY TOWARDS ISOLATED PERFUSED RAT LIVERS - THE ROLE OF LIPID-PEROXIDATION

被引:57
作者
YOUNES, M [1 ]
STRUBELT, O [1 ]
机构
[1] MED UNIV LUBECK,INST TOXICOL,W-2400 LUBECK,GERMANY
关键词
CALCIUM; GLUTATHIONE; HEPATOTOXICITY; ISOLATED PERFUSED LIVER; LIPID PEROXIDATION; VANADATE;
D O I
10.1016/0300-483X(91)90178-4
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The toxic potential of sodium orthovanadate towards isolated perfused rat livers was investigated at a dose of 2 mmol/l. In livers from fasted rats, vanadate led to a release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH) and mitochondrial (glutamate dehydrogenase (GLDH)) enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an augmented formation and release of thiobarbituric acid-reactive material by the liver. Furthermore, a marked inhibition of oxygen consumption was observed. Vanadate-induced vasoconstriction resulted in a progressive decrease in perfusate flow rate. Control experiments with similarly reduced flow rates led to a comparable reduction in oxygen consumption. GPT and LDH release and hepatic glutathione depletion were also evident, though to a lesser extent than in the presence of vanadate, but no increase in GLDH release, in tissue calcium content or TBA-reactive material in the liver or the perfusate were observed. Thus, indirect toxic effects due to a reduced flow rate contribute only partly to vanadate hepatotoxicity and do not affect mitochondrial integrity. Omission of calcium from the perfusate did not prevent hepatotoxic responses to vanadate, although less calcium was present in the treated livers than in the control organs, indicating that calcium influx is not involved in vanadate-induced hepatotoxicity in the intact organ, in contrast to isolated hepatocytes [13]. Feeding the animals, resulting in an activation of anaerobic energy conservation reactions, strongly attenuated vanadate hepatotoxicity indicating that the energetic status of the liver is the main target of vanadate. Superoxide dismutase did not affect the hepatotoxic responses of livers from fasted rats towards vanadate, while allopurinol and deferrioxamine inhibited lipid peroxidation and hepatotoxicity due to vanadate. The strong correlation between induction of lipid peroxidation and hepatotoxicity and the inhibition of both processes in parallel by antioxidants are suggestive of a causative role for lipid peroxidation in vanadate-induced hepatotoxicity.
引用
收藏
页码:63 / 74
页数:12
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