Nakamura H
Hokkaido Igaku Zasshi. 1976 Jul;51(4):289-97.
Amimal experiments were conducted to elucidate the mechanism responsible for lowering the blood cholesterol level of mice by clofibrate (CPIB). 1. Cholesterol biosynthesis: (1) Cholesterol biosynthesis from acetate-1-14C or mevalonic acid-2-14C in liver, blood, intestine and kidney was not changed when 0.3 X 10(-3) M CPIB was added to the liver homogenate, when mice were fed on a basal diet containing 0.1% CPIB for 10 days or fed on a basal diet containing 0.5% CPIB for 18 days, and when fed on a diet containing both cholesterol and 0.5% CPIB for 10 days. (2) However, the cholesterol biosynthesis in liver and blood of the mice fed on the basal diet containing 0.5% CPIB for 10 days was suppressed at the step of conversion of acetate to mevalonic acid. In addition, since the incorporation of acetate-1-14C into squalene and of mevalonic acid-2-14C into squalene and ianosterol was suppressed in the liver homogenate of the mice, the cholesterol biosynthesis was depressed at the step of conversion of mevalonic acid to squalene. Therefore, CPIB depressed the cholesterol biosynthesis at both steps before and after mevalonic acid. 2. The fecal excretion of the sterol-14C and bile acid-14C derived from injected cholesterol -14C: When mice injected with cholesterol-14C were kept on a basal diet or cholesterol-added diet containing 0.1% CPIB, the excretion of sterol-14C and nonsaponifiable materials-14C in the feces was markedly increased in the case of basal diet as well as cholesterol-added diet. However, the excretion of total bile acid-14C was not changed when mice were fed on the basal diet, but it was markedly increased when fed on the cholesterol-added diet. The specific radioactivity of sterol-14C in blood 30 days after injection was reduced in the basal diet or the cholesterol-added diet, while that in liver was not changed or increased. Total cholesterol level in blood 30 days after injection was not affected in mice fed on basal diet and was reduced in mice fed on the cholesterol-added diet. From the above facts, the lowering effective of CPIB on the blood cholesterol level appears to depend not on the alteration of the cholesterol biosynthesis but on the increase of excretion of sterol derived from the tissue cholesterol in the feces.
进行动物实验以阐明氯贝丁酯（CPIB）降低小鼠血液胆固醇水平的机制。1. 胆固醇生物合成：（1）当向肝匀浆中添加0.3×10⁻³M CPIB时，当小鼠在含0.1% CPIB的基础饲料中喂养10天或在含0.5% CPIB的基础饲料中喂养18天时，以及当在含胆固醇和0.5% CPIB的饲料中喂养10天时，肝脏、血液、肠道和肾脏中由乙酸-1-¹⁴C或甲羟戊酸-2-¹⁴C合成胆固醇的过程未发生变化。（2）然而，在含0.5% CPIB的基础饲料中喂养10天的小鼠的肝脏和血液中，胆固醇生物合成在乙酸转化为甲羟戊酸的步骤受到抑制。此外，由于在小鼠的肝匀浆中，乙酸-1-¹⁴C掺入角鲨烯以及甲羟戊酸-2-¹⁴C掺入角鲨烯和羊毛甾醇受到抑制，胆固醇生物合成在甲羟戊酸转化为角鲨烯的步骤受到抑制。因此，CPIB在甲羟戊酸之前和之后的两个步骤均抑制了胆固醇生物合成。2. 注射胆固醇-¹⁴C衍生的甾醇-¹⁴C和胆汁酸-¹⁴C的粪便排泄：当给注射了胆固醇-¹⁴C的小鼠喂食基础饲料或含0.1% CPIB的添加胆固醇饲料时，无论基础饲料还是添加胆固醇饲料，粪便中甾醇-¹⁴C和非皂化物质-¹⁴C的排泄均显著增加。然而，当小鼠喂食基础饲料时，总胆汁酸-¹⁴C的排泄未发生变化，但当喂食添加胆固醇饲料时则显著增加。注射后30天血液中甾醇-¹⁴C的比放射性在基础饲料或添加胆固醇饲料中降低，而肝脏中的比放射性未变化或升高。注射后30天，喂食基础饲料的小鼠血液中的总胆固醇水平未受影响，而喂食添加胆固醇饲料的小鼠血液中的总胆固醇水平降低。基于上述事实，CPIB对血液胆固醇水平的降低作用似乎并非取决于胆固醇生物合成的改变，而是取决于粪便中组织胆固醇衍生的甾醇排泄增加。
