Burton P M, Swinney D C, Heller R, Dunlap B, Chiou M, Malonzo E, Haller J, Walker K A, Salari A, Murakami S
Institute of Biochemistry and Cell Biology, Syntex Research, Palo Alto, CA 94304, USA.
Biochem Pharmacol. 1995 Aug 8;50(4):529-44. doi: 10.1016/0006-2952(95)00152-p.
Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, human fibroblasts, hamster hepatocytes and hamster liver, by inhibiting the cytochrome P450 enzyme lanosterol 14 alpha-demethylase. When administered orally to hamsters fed regular chow, RS-21607 (50 mg/kg/day) lowered serum cholesterol in a dose-dependent manner (ED50 = 62 mg/kg) in a period of 1 week. It preferentially lowered low density lipoprotein (LDL) cholesterol and apo B relative to high density lipoprotein (HDL) cholesterol and apo A-1. It also lowered plasma cholesterol levels in hamsters fed a high saturated fat and cholesterol diet. RS-21607 inhibited hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity in hamsters in a dose-dependent manner (ED50 = 31 mg/kg), and this was highly correlated with serum cholesterol lowering (r = 0.97). Cholesterol lowering by azalanstat and cholestyramine was additive, and the increase in HMG-CoA reductase brought about by cholestyramine was attenuated significantly by azalanstat. In vitro studies with HepG2 cells indicated that this modulation of reductase activity was indirect, occurring at a post-transcriptional step, and it is proposed that a regulatory oxysterol derived from dihydrolanosterol (or lanosterol) may be responsible for this regulation. Azalanstat does not appear to lower circulating cholesterol in the hamster by up-regulation of the hepatic LDL receptor, suggesting that other mechanisms are involved. Orally administered azalanstat (50-75 mg/kg) stimulated hepatic microsomal cholesterol 7 alpha-hydroxylase activity by 50-400% in hamsters, and it is postulated that this may result from modified cholesterol absorption and bile acid synthesis.
抑制肝脏胆固醇生物合成的药物可降低实验动物和人类的循环胆固醇水平，在预防动脉粥样硬化方面可能具有药理学重要性。阿扎兰司他（RS - 21607）是一种合成咪唑，已表明它通过抑制细胞色素P450酶羊毛甾醇14α - 去甲基酶，来抑制HepG2细胞、人成纤维细胞、仓鼠肝细胞和仓鼠肝脏中的胆固醇合成。当以口服方式给予喂食普通饲料的仓鼠时，RS - 21607（50毫克/千克/天）在1周内以剂量依赖性方式降低血清胆固醇（ED50 = 62毫克/千克）。相对于高密度脂蛋白（HDL）胆固醇和载脂蛋白A - 1，它优先降低低密度脂蛋白（LDL）胆固醇和载脂蛋白B。它还降低了喂食高饱和脂肪和胆固醇饮食的仓鼠的血浆胆固醇水平。RS - 21607以剂量依赖性方式抑制仓鼠肝脏微粒体羟甲基戊二酰辅酶A（HMG - CoA）还原酶活性（ED50 = 31毫克/千克），且这与血清胆固醇降低高度相关（r = 0.97）。阿扎兰司他和考来烯胺降低胆固醇的作用是相加的，考来烯胺引起的HMG - CoA还原酶增加被阿扎兰司他显著减弱。对HepG2细胞的体外研究表明，这种还原酶活性的调节是间接的，发生在转录后步骤，并且有人提出源自二氢羊毛甾醇（或羊毛甾醇）的一种调节性氧化甾醇可能负责这种调节。阿扎兰司他似乎不是通过上调肝脏LDL受体来降低仓鼠的循环胆固醇，这表明涉及其他机制。口服阿扎兰司他（50 - 75毫克/千克）可使仓鼠肝脏微粒体胆固醇7α - 羟化酶活性提高50 - 400%，据推测这可能是由于胆固醇吸收和胆汁酸合成改变所致。
