INHIBITION BY PERHEXILINE OF OXIDATIVE-PHOSPHORYLATION AND THE BETA-OXIDATION OF FATTY-ACIDS - POSSIBLE ROLE IN PSEUDOALCOHOLIC LIVER-LESIONS
INHIBITION BY PERHEXILINE OF OXIDATIVE-PHOSPHORYLATION AND THE BETA-OXIDATION OF FATTY-ACIDS - POSSIBLE ROLE IN PSEUDOALCOHOLIC LIVER-LESIONS
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DOI：
10.1016/0270-9139(94)90296-8
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发表时间：
1994-04-01
期刊：
影响因子：
13.5
通讯作者：
PESSAYRE, D
中科院分区：
文献类型：
--
作者：
DESCHAMPS, D;DEBECO, V;PESSAYRE, D
为了更好地了解人类假性酒精性肝损伤的机制，我们确定了perhexiline对小鼠和大鼠线粒体功能的影响。第一系列的研究表明，质子化perhexiline进入小鼠线粒体沿着线粒体膜电位。线粒体基质中质子的释放导致氧化磷酸化解偶联，哌己西林的蓄积抑制呼吸链的复合物I和II，降低体外ATP形成，并降低小鼠体内和体外长链、中链和短链脂肪酸的线粒体β-氧化。在培养的大鼠肝细胞中，暴露于25 mumol/L perhexiline 24小时显着降低肝细胞ATP和细胞活力。暴露于5 mumol/L perhexiline并没有改变ATP和活力，但减少了β-氧化棕榈酸均匀标记的碳14的38%，增加了98%的肝细胞甘油三酯水平，并产生微泡脂肪变性后72小时的文化。我们得出结论，perhexiline是集中在线粒体内，在那里它抑制氧化磷酸化和线粒体β-氧化脂肪酸。这些作用可能导致人类坏死、脂肪变性和可能的某些其他假酒精性肝病变的发展。
In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.