Pessayre D, Mansouri A, Haouzi D, Fromenty B
INSERM U481 and Centre de Recherche sur les Hépatites Virales de l'Association Claude Bernard, Hôpital Beaujon, Clichy, France.
Cell Biol Toxicol. 1999;15(6):367-73. doi: 10.1023/a:1007649815992.
Mitochondria are involved in fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, which provide most of the cell energy. Mitochondria are also the main source of reactive oxygen species in the cell and are involved in cell demise through opening of the mitochondrial permeability transition pore. It was therefore to be expected that mitochondrial dysfunction could be a major mechanism of drug-induced liver disease. Microvesicular steatosis (which may cause liver failure, coma, and death) is the consequence of severe impairment of mitochondrial beta-oxidation. Endogenous compounds (such as cytokines or female sex hormones) or xenobiotics (including toxins such as ethanol and drugs such as aspirin, valproic acid, ibuprofen, or zidovudine) can inhibit beta-oxidation directly or through a primary effect on the mitochondrial genome or the respiratory chain itself. In some patients, infections and cytokines, or inborn errors of beta-oxidation enzymes or the mitochondrial genome, may favor the appearance of drug-induced microvesicular steatosis. Nonalcoholic steatohepatitis may develop under conditions causing prolonged, microvesicular, and/or macrovacuolar steatosis. In this condition, chronic impairment of mitochondrial beta-oxidation (causing steatosis) and the respiratory chain (increasing the production of ROS) lead to lipid peroxidation, which, in turn, may cause the diverse lesions of steatohepatitis, namely, necrosis, inflammation, Mallory's bodies, and fibrosis. Finally, mitochondria are involved in several forms of drug-induced cytolytic hepatitis, through inhibition or uncoupling of respiration or through a drug-induced or reactive metabolite-induced mitochondrial permeability transition. The latter effect commits hepatocytes to either apoptosis or necrosis, depending on the number of organelles that have undergone the permeability transition.
线粒体参与脂肪酸β-氧化、三羧酸循环和氧化磷酸化，这些过程提供了细胞的大部分能量。线粒体也是细胞中活性氧的主要来源，并通过线粒体通透性转换孔的开放参与细胞死亡。因此，可以预期线粒体功能障碍可能是药物性肝病的主要机制。微泡性脂肪变性（可能导致肝衰竭、昏迷和死亡）是线粒体β-氧化严重受损的结果。内源性化合物（如细胞因子或女性性激素）或外源性物质（包括毒素如乙醇和药物如阿司匹林、丙戊酸、布洛芬或齐多夫定）可直接或通过对线粒体基因组或呼吸链本身的原发性作用抑制β-氧化。在一些患者中，感染和细胞因子，或β-氧化酶或线粒体基因组的先天性缺陷，可能有利于药物性微泡性脂肪变性的出现。非酒精性脂肪性肝炎可能在导致长期、微泡性和/或大泡性脂肪变性的条件下发展。在这种情况下，线粒体β-氧化的慢性损害（导致脂肪变性）和呼吸链（增加活性氧的产生）导致脂质过氧化，进而可能导致脂肪性肝炎的各种病变，即坏死、炎症、马洛里小体和纤维化。最后，线粒体通过抑制呼吸或使其解偶联，或通过药物诱导或反应性代谢物诱导的线粒体通透性转换，参与几种形式的药物性细胞溶解性肝炎。后一种效应使肝细胞发生凋亡或坏死，这取决于经历通透性转换的细胞器数量。
