Suzumura K, Odawara A, Yasuhara M, Tanaka K, Narita H, Suzuki T
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Biol Pharm Bull. 1999 Sep;22(9):971-4. doi: 10.1248/bpb.22.971.
Fluvastatin is a synthetic hypolipidemic drug which inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. We compared in vitro the antioxidative effects of two enantiomers (3R, 5S and 3S, 5R) of fluvastatin, which is clinically used as a racemic mixture, on copper ion-induced oxidation of human low-density lipoprotein (LDL). Although 3R,5S-enantiomer of fluvastatin has 30-fold stronger inhibitory activity on HMG-CoA reductase than its optical counterpart, the antioxidative effects of these enantiomers on copper ion-induced LDL oxidation were similar. The antioxidative effects of the metabolites of fluvastatin (M2, M3, M4 and M7) on the copper ion-induced LDL oxidation were also investigated. All the metabolites tested showed an inhibitory effect on this system. Among them, the effects of M2 and M3, which have a phenolic hydroxyl group in each indole moiety, were strong and their potencies were 30-50 times greater than that of fluvastatin. We conclude that not only 3R,5S-enantiomer of fluvastatin but also its optical counterpart and the metabolites also have a potential to show the anti-atherosclerotic effect through their antioxidative activities on lipid peroxidation.
氟伐他汀是一种合成的降血脂药物，可抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶。我们在体外比较了临床上作为消旋混合物使用的氟伐他汀的两种对映体（3R，5S和3S，5R）对铜离子诱导的人低密度脂蛋白（LDL）氧化的抗氧化作用。尽管氟伐他汀的3R，5S-对映体对HMG-CoA还原酶的抑制活性比其旋光对应体强30倍，但这些对映体对铜离子诱导的LDL氧化的抗氧化作用相似。还研究了氟伐他汀代谢产物（M2、M3、M4和M7）对铜离子诱导的LDL氧化的抗氧化作用。所有测试的代谢产物均对该系统显示出抑制作用。其中，在每个吲哚部分都有酚羟基的M2和M3的作用较强，其效力比氟伐他汀高30-50倍。我们得出结论，不仅氟伐他汀的3R，5S-对映体，而且其旋光对应体和代谢产物也有可能通过其对脂质过氧化的抗氧化活性而显示出抗动脉粥样硬化作用。
