Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation
Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation
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DOI：
10.1016/s0021-9150(98)00032-x
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发表时间：
1998-06-01
期刊：
影响因子：
5.3
通讯作者：
Newton, RS
中科院分区：
文献类型：
--
作者：
Aviram, M;Rosenblat, M;Newton, RS
高脂血症患者动脉粥样硬化风险增加可能是其血浆脂蛋白氧化性增强的结果。我们之前已经证明，降胆固醇药物治疗，包括 3-羟基-3-甲基-戊二酰辅酶 A (HMG-CoA) 还原酶抑制剂和降甘油三酯药物苯扎贝特，可显着降低从高脂血症患者中分离出的低密度脂蛋白 (LDL) 的氧化敏感性。尽管所有这些药物都无法在体外获得这种抗氧化作用，但体内形成的活性药物代谢物可能会影响脂蛋白的氧化性。因此，我们试图分析阿托伐他汀和吉非贝齐以及特定羟基化代谢物对 LDL、极低密度脂蛋白 (VLDL) 和高密度脂蛋白 (HDL) 氧化敏感性的影响。由铜离子 (10 μM CuSO4)、自由基生成系统 2'-2'-偶氮双 2-脒基丙烷盐酸盐 (5 mM AAPH) 或 J-774A.1 巨噬细胞样细胞系诱导的 LDL 氧化不会被阿托伐他汀或吉非罗齐的母体形式抑制，但以浓度依赖性方式被显着抑制 (57-97%)，阿托伐他汀的邻羟基和对羟基代谢物以及吉非贝齐的对羟基代谢物（代谢物 I）的药理学浓度。在联合使用阿托伐他汀邻羟基代谢物和吉非贝齐代谢物 I 时，发现对 LDL 氧化性具有相加抑制作用。对于上述氧化系统中 VLDL 和 HDL 对氧化的敏感性，获得了上述代谢物的类似抑制作用 (37-96%)。这些代谢物对 LDL、VLDL 和 HDL 氧化的抑制作用可能与其自由基清除活性以及（主要是吉非贝齐代谢物 I）与其金属离子螯合能力有关。此外，HDL 氧化的抑制与 HDL 相关的对氧磷酶活性的保存有关。我们得出的结论是，阿托伐他汀羟基代谢物和吉非贝齐代谢物 I 具有有效的抗氧化潜力，因此可以保护 LDL、VLDL 和 HDL 免受氧化。我们假设，除了有益的脂质调节活性之外，两种药物的特定代谢物还可能通过其抗氧化特性降低脂蛋白致动脉粥样硬化的可能性。 (C) 1998 Elsevier Science Ireland Ltd. 保留所有权利。
Increased atherosclerosis risk in hyperlipidemic patients may be a result of the enhanced oxidizability of their plasma lipoproteins. We have previously shown that hypocholesterolemic drug therapy, including the 3-hydroxy-3-methyl-glutaryl CoenzymeA (HMG-CoA) reductase inhibitors, and the hypotriglyceridemic drug bezafibrate, significantly reduced the enhanced susceptibility to oxidation of low density lipoprotein (LDL) isolated from hyperlipidemic patients. Although this antioxidative effect could not be obtained in vitro with all of these drugs, the active drug metabolites, which are formed in vivo, could affect lipoprotein oxidizability. We thus sought to analyze the effect of atorvastatin and gemfibrozil, as well as specific hydroxylated metabolites, on the susceptibility of LDL, very low density lipoprotein (VLDL), and high density lipoprotein (HDL) to oxidation. LDL oxidation induced by either copper ions (10 mu M CuSO4), by the free radical generator system 2'-2'-azobis 2-amidino propane hydrochloride (5 mM AAPH), or by the J-774A.1 macrophage-like cell line, was not inhibited by the parent forms of atorvastatin or gemfibrozil, but was substantially inhibited (57-97%), in a concentration-dependent manner, by pharmacological concentrations of the o-hydroxy and the p-hydroxy metabolites of atorvastatin, as well as by the p-hydroxy metabolite (metabolite I) of gemfibrozil. On using the atorvastatin o-hydroxy metabolite and gemfibrozil metabolite I in combination an additive inhibitory effect on LDL oxidizability was found. Similar inhibitory effects (37-96%) of the above metabolites were obtained for the susceptibility of VLDL and HDL to oxidation in the oxidation systems outlined above. The inhibitory effects of these metabolites on LDL, VLDL, and HDL oxidation could be related to their free radical scavenging activity, as well as (mainly for the gemfibrozil metabolite I) to their metal ion chelation capacities. In addition, inhibition of HDL oxidation was associated with the preservation of HDL-associated paraoxonase activity. We conclude that atorvastatin hydroxy metabolites, and gemfibrozil metabolite I possess potent antioxidative potential, and as a result protect LDL, VLDL, and HDL from oxidation. We hypothesize that in addition to their beneficial lipid regulating activity, specific metabolites of both drugs may also reduce the atherogenic potential of lipoproteins through their antioxidant properties. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.