EFFECTS OF INHIBITORS OF HYDROXYMETHYLGLUTARYL COENZYME-A REDUCTASE ON COENZYME-Q AND DOLICHOL BIOSYNTHESIS

Inhibitors of hydroxymethylglutaryl coenzyme A reductase are used clin ically to decrease blood levels of low-density lipoprotein cholesterol in hypercholesterolemic patients. However, little is known about the possible effects of these inhibitors on dolichol and cholesterol synth esis. Oral administration of mevinolin to rats was found here to decre ase dolichol, dolichyl-P and coenzyme Q levels in the heart and skelet al muscle and to increase the hepatic dolichol level while decreasing the coenzyme Q content in this same organ. The amounts of dolichyl-P d ecreased in heart and muscle and increased in brain. Intraperitoneal a dministration also affected the levels of these lipids. The concentrat ions of blood lipids were not modified in the same manner as tissue li pids. Analysis of individual enzyme activities and of incorporation of [H-3]acetate into various lipids of liver and brain slices demonstrat ed that both up- and down-regulation of different proteins occur in va rious tissues, resulting in modifications in lipid synthesis. Hypercho lesterolemic patients were found to have high blood coenzyme Q levels, which are decreased upon pravastatin treatment, although they are sti ll above control values. It appears that these HMG-coenzyme A reductas e inhibitors do not selectively lower cholesterol levels, but that the y also modify the dolichol and coenzyme Q content and synthesis both i n the liver and various other tissues.