Effects of chlorophenoxyisobutyrate on the synthesis and metabolism of cholesterol in man

Abstract

The effects of an oral administration of clofibrate 500 mg. four times a day on plasma cholesterol were studied in 16 subjects on constant dietary intake. The lipoprotein patterns were normal in four, Type II in five and Type IV in seven subjects. There was a rapid decline in the levels of plasma cholesterol and in 15 days these had stabilized at 78 ± 5 per cent of the pretreatment values. No differences between the Type II, Type IV or normals were seen in these short-term studies. Eight subjects (three normal, two Type II and three Type IV) were given a mixture containing sodium acetate-1- 14C and DL mevalonate-2- 3H lactone intravenously, once before and once after 10 days of treatment with clofibrate. The peak specific activity of 14C (from acetate-1- 14C) in plasma cholesterol was decreased (28.5 ± 14.6%) but that of 3H (from mevalonate-2- 3H) was not affected by the treatment. The 14C specific activity of biliary cholesterol was decreased even more than that of plasma cholesterol supporting the hypothesis that the site of action of clofibrate in the hepatic synthesis of cholesterol in man is between acetate and mevalonate. The drug did not have any effect on the fractional turnover rates of plasma cholesterol esters; but, their net turnover rates were reduced on account of the decrease in their pool size. The ratios of 3 H 14 C in cholesterol during the first few hours after the injection of the radioactive precursors were not constant from hour to hour. There was also a steady difference in the 3 H 14 C ratios between plasma and bile cholesterol at all times. This suggested to us that the relative incorporation of the two precursors in different cholesterol tissue pools in rapid equilibrium with plasma cholesterol was different.