Alegret M, Silvestre J S
Unitat de Farmacologia, Departament de Farmacologia i Quimica Terapeutica, Facultat de Farmacia, Universitat de Barcelona, Barcelona, Spain.
Methods Find Exp Clin Pharmacol. 2006 Nov;28(9):627-56. doi: 10.1358/mf.2006.28.9.1003573.
Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects", and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.
他汀类药物是处方最广泛的降胆固醇药物，被认为是预防冠心病和动脉粥样硬化的一线治疗药物。他汀类药物通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶发挥作用，该酶是内源性胆固醇生物合成中的限速酶，催化HMG-CoA还原为甲羟戊酸。事实证明，抑制这种酶对降低人体血浆总胆固醇、低密度脂蛋白胆固醇和甘油三酯水平有效，因此可用于治疗动脉粥样硬化和血脂异常疾病。然而，他汀类药物的临床益处似乎超出了其降血脂作用。除了减少胆固醇生物合成外，他汀类药物抑制甲羟戊酸还会导致重要中间体的合成减少，如类异戊二烯焦磷酸法呢酯和香叶基香叶基焦磷酸。这些中间体参与多种蛋白质（如Ras、Rho、Rac）的翻译后异戊二烯化，这些蛋白质调节多种细胞过程，包括细胞信号传导、分化和增殖。鉴于这些异戊二烯化蛋白质在内皮功能、动脉粥样硬化斑块稳定性、血小板活性、凝血、氧化以及炎症和免疫反应中的核心作用，可以预期这些化合物可能在包括心血管疾病、骨质疏松症、阿尔茨海默病及相关血管性痴呆、病毒和细菌感染等广泛疾病中发挥多种有益作用。本文总结了他汀类药物这些与降胆固醇无关的作用，即“多效性作用”及其潜在机制，以及有助于评估他汀类药物作用的临床前实验方法。
