Protective effects of coenzyme Q10 on decreased oxidative stress resistance induced by simvastatin
Protective effects of coenzyme Q10 on decreased oxidative stress resistance induced by simvastatin
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DOI：
10.3164/jcbn.40.194
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发表时间：
2007-05-01
影响因子：
2.4
通讯作者：
Okamoto, Tadashi
中科院分区：
文献类型：
--
作者：
Kettawan, Aikkarach;Takahashi, Takayuki;Okamoto, Tadashi
研究了3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoA reductase，HMG-CoA reductase）抑制剂辛伐他汀（simvastatin）对大鼠抗氧化应激能力的影响及辅酶Q（CoQ）的保护作用。当小鼠口服辛伐他汀时，与对照组相比，血清、肝脏和心脏中的氧化和还原辅酶Q（9）和辅酶Q（10）水平显著降低。辛伐他汀还可显著增加肝脏和心脏线粒体中抗坏血酸铁诱导的硫代巴比妥酸反应物质的水平。此外，辛伐他汀处理的培养心肌细胞表现出较低的抗氧化应激，减少时间停止自发跳动响应H2 O2的添加，并降低对电场刺激的反应。这些结果表明，口服辛伐他汀抑制辅酶Q的生物合成，其与胆固醇至焦磷酸法呢酯的生物合成途径相同，从而损害具有抗氧化活性的还原辅酶Q的生理功能。然而，辛伐他汀诱导的这些不良反应可通过CoQ（10）与辛伐他汀联合给药减轻。辛伐他汀还降低了NADPH-CoQ还原酶的活性，这是一种将氧化CoQ转化为相应还原CoQ的生物酶，而CoQ（10）给药改善了这一点。这些发现也可能支持CoQ（10）与他汀类药物联合给药的疗效。
The effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), on oxidative stress resistance and the protective effects of coenzyme Q (CoQ) were investigated. When simvastatin was administered orally to mice, the levels of oxidized and reduced CoQ(9) and CoQ(10) in serum, liver, and heart, decreased significantly when compared to those of control. The levels of thiobarbituric acid reactive substances induced by Fe2+-ascorbate in liver and heart mitochondria also increased significantly with simvastatin. Furthermore, cultured cardiac myocytes treated with simvastatin exhibited less resistance to oxidative stress, decreased time to the cessation of spontaneous beating in response to H2O2 addition, and decreased responsiveness to electrical field stimulation. These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.