Endo A, Tsujita Y, Kuroda M, Tanzawa K
Biochim Biophys Acta. 1979 Nov 21;575(2):266-76.
ML-263B (compactin), a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, is very effective in lowering serum cholesterol levels in animal species such as hens, dogs, monkeys and man. In the present studies, the effect of this drug on cholesterol metabolism in several strains of mice and rats was studied. The results indicate that, when administered for a longer period, the drug showed no hypocholesterolemic activity in these species under either normo- or hypercholesterolemic conditions, except for rats treated with the detergent Triton WR-1339. The administration of ML-236B caused a significant decrease in fecal excretion of bile acids and in the hepatic levels of cholesterol 7 alpha-hydroxylase, and produced a marked increase in hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase activity, resulting in no inhibition of hepatic sterol synthesis, even in the presence of the drug in the active form(s). It is concluded that the lack of hypocholesterolemic activity of ML-236B in mice and rats could, at least partly, be explained by these unexpected results.
ML - 263B（美伐他汀）是3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶的竞争性抑制剂，对降低母鸡、狗、猴子和人类等动物物种的血清胆固醇水平非常有效。在本研究中，研究了这种药物对几种小鼠和大鼠品系胆固醇代谢的影响。结果表明，长期给药时，除用去污剂Triton WR - 1339处理的大鼠外，在正常或高胆固醇血症条件下，该药物在这些物种中均未表现出降胆固醇活性。给予ML - 236B导致胆汁酸粪便排泄量和肝脏胆固醇7α - 羟化酶水平显著降低，并使肝脏3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶活性水平显著升高，即使存在活性形式的药物，也不会抑制肝脏甾醇合成。得出的结论是，ML - 236B在小鼠和大鼠中缺乏降胆固醇活性至少部分可以由这些意外结果来解释。
