[Studies on the mechanism of lowering of the cholesterol level by ethyl-alpha-p-chlorophenoxy-isobutyrate (clofibrate) (author's transl)].

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.