Marques Ana C, Busanello Estela N B, de Oliveira Diogo N, Catharino Rodrigo R, Oliveira Helena C F, Vercesi Anibal E
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.
Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, Brazil.
Front Pharmacol. 2018 Jun 27;9:685. doi: 10.3389/fphar.2018.00685. eCollection 2018.
Statins are the preferred therapy to treat hypercholesterolemia. Their main action consists of inhibiting the cholesterol biosynthesis pathway. Previous studies report mitochondrial oxidative stress and membrane permeability transition (MPT) of several experimental models submitted to diverse statins treatments. The aim of the present study was to investigate whether chronic treatment with the hydrophilic pravastatin induces hepatotoxicity in LDL receptor knockout mice (), a model for human familial hypercholesterolemia. We evaluated respiration and reactive oxygen production rates, cyclosporine-A sensitive mitochondrial calcium release, antioxidant enzyme activities in liver mitochondria or homogenates obtained from mice treated with pravastatin for 3 months. We observed that pravastatin induced higher HO production rate (40%), decreased activity of aconitase (28%), a superoxide-sensitive Krebs cycle enzyme, and increased susceptibility to Ca-induced MPT (32%) in liver mitochondria. Among several antioxidant enzymes, only glucose-6-phosphate dehydrogenase (G6PD) activity was increased (44%) in the liver of treated mice. Reduced glutathione content and reduced to oxidized glutathione ratio were increased in livers of pravastatin treated mice (1.5- and 2-fold, respectively). The presence of oxidized lipid species were detected in pravastatin group but protein oxidation markers (carbonyl and SH- groups) were not altered. Diet supplementation with the antioxidants CoQ10 or creatine fully reversed all pravastatin effects (reduced HO generation, susceptibility to MPT and normalized aconitase and G6PD activity). Taken together, these results suggest that 1- pravastatin induces liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and 2- the co-treatment with safe antioxidants neutralize these side effects.
他汀类药物是治疗高胆固醇血症的首选疗法。它们的主要作用是抑制胆固醇生物合成途径。先前的研究报道了多种接受不同他汀类药物治疗的实验模型中的线粒体氧化应激和膜通透性转换（MPT）。本研究的目的是调查亲水性普伐他汀的长期治疗是否会在低密度脂蛋白受体敲除小鼠（一种人类家族性高胆固醇血症模型）中诱发肝毒性。我们评估了呼吸和活性氧生成速率、环孢素A敏感的线粒体钙释放、从用普伐他汀治疗3个月的小鼠获得的肝线粒体或匀浆中的抗氧化酶活性。我们观察到普伐他汀诱导肝线粒体中更高的HO生成速率（40%）、乌头酸酶活性降低（28%），乌头酸酶是一种对超氧化物敏感的三羧酸循环酶，并且增加了对Ca诱导的MPT的敏感性（32%）。在几种抗氧化酶中，仅治疗小鼠肝脏中的葡萄糖-6-磷酸脱氢酶（G6PD）活性增加（44%）。普伐他汀治疗小鼠的肝脏中还原型谷胱甘肽含量和还原型与氧化型谷胱甘肽的比率增加（分别为1.5倍和2倍）。在普伐他汀组中检测到氧化脂质种类的存在，但蛋白质氧化标记物（羰基和SH基团）未改变。用抗氧化剂辅酶Q10或肌酸补充饮食完全逆转了所有普伐他汀的作用（减少HO生成、对MPT的敏感性并使乌头酸酶和G6PD活性正常化）。综上所述，这些结果表明：1- 普伐他汀诱导肝线粒体氧化还原失衡，这可能解释了少数患者中报道的肝脏副作用；2- 与安全抗氧化剂联合治疗可中和这些副作用。
