降低膽固醇與抗動脈粥狀硬化藥物

Recent Advances in the Development of Hypocholesterolemic and Anti-Atherosclerotic Drugs

蕭明熙(Ming-Shi Shiao)

《化學》 52卷4期 (1994/12) Pp. 442-453

https://doi.org/10.6623/chem.1994057

摘要

人體血漿中的低密度脂蛋白濃度值與動脈粥狀硬化及心血管疾病呈正相關。就人類肝臟而言，膽固醇恆定是取決於低密度脂蛋白受體引入的能力與3-羥-3-甲基麩酸輔酶A還原酶(簡稱HMG-CoA還原酶)可呈協調式之回饋調控，HMG-CoA還原酶是膽固醇生合途徑上之限速悔，最近已有四種HMG-CoA reductase抑制劑型態藥物研發成功，可叫降低血液中的低密度脂蛋白膽固醇值，甚至減緩脈動粥狀硬化的進行。另外的新藥研發，諸如：抑制小腸對膽固醇的吸收、阻斷膽酸腸肝循環和後mevalonic acid階段的酶抑制劑，亦有許多藥廠在進行中。最近分子與細胞生物學進展顯示：動脈粥狀硬化涉及內璧細胞功能變異、單核細胞侵入並活化成巨噬細胞、及平滑肌細胞移位與增生。許多種細胞激素、細胞黏附分子、生長因子、與血管調節分子均參與此病因形成，而遭過氧化破壞的低密度脂蛋白(簡稱OX-LDL)則紛演貫穿各惡化扇趨勢，因而導致動脈粥狀硬化的關鍵角色。OX-LDL對內壁細胞有胞毒性，且會誘引及活化單核細胞成為巨噬細胞，後者藉由表現清除受體而吞入OX-LDL，上述分子醫學的進展為未來治療動脈粥狀硬化呈現新的曙光。除了基因治療之外，發展可抑制低密度脂蛋白的抗氧化劑，以及可抑制OX-LDL遭清除受體吞入的專一性抑制劑，可能均甚具潛力，本文將闡述這方面的一些新進發展。

並列摘要

Elevation of plasma low density lipoprotein (LOL) is positively correlated with atherosclerosis and coronary heart disease. In human, cholesterol homeostasis is achieved by the coordination and feedback regulation of the receptor-mediated LDL uptake and 3-hydroxy-3-methyIglutaryl coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in the cholesterol biosynthetic pathway, in the liver. Recently, several HMG-CoA reductase inhibitors have been developed to lower plasma LDL cholesterol and even to reduce the progression of atherosclerosis. Other approaches such as inhibition of cholesterol absorption in the intestine, interruption of enterohepatic circulation of bile acids, and inhibition of post-mevalonate enzymes in the cholesterol biosynthetic pathway are currently underway. Recent advances in molecular and cell biology have demonstrated that the pathogenesis of atherosclerosis involves endothelium dysfunction, infiltration of monocytes and activation into macrophages, and smooth muscle cell migration and proliferation. Many cytokines, cell adhesion molecules, growth factors, and vasoregulatory molecules participate in the cascade. Oxidatively modified LDL (OX-LDL) plays a pivotal role in the initiation and progression of atherosclerosis. OX- LOL is cytotoxic to endothelial cells and can recruit and activate monocytes into macrophages. OX-LDL is readily taken by macrophages through the scavenger receptors. Current advance s in molecular medicine have shed light on many new approaches to the treatment of atherosclerosis. Besides gene therapy, the development of antioxidants to inhibit LDL lipid peroxidation and specific inhibitors to interrupt the uptake of OX-LOL by macrophages may become possible. These new trends of drug development are discussed.