INHIBITION OF CHOLESTEROL SYNTHESIS IN RATS by James R. Clark A Thesis Submitted to the . COMMITTEE ON AGRICULTURAL BIOCHEMISTRY AND NUTRITION

The purpose of this research was to find a derivative of 3-hydroxy-3-methyIglutaric acid which would prevent the reduction of 3-hydroxy-3-methylglutaric Coenzyme A to mevalonic acid by competitively inhibiting the enzyme 3-hydroxy-3-methylglutaric Coenzyme A reductase* Reduction of this reaction would inhibit the synthesis of cholesterol at a strategic site since this is the first irreversible step in the biosynthesis of cholesterol* This is the only site which will not interfere with the synthesis of fatty acids or ketone bodies and will notcause a build up of pre­ cursors which are potentially pathological* Accumulation of precursors has occurred when inhibitors blocked reactions past the formation of mevalonic acid. Two examples of this type of inhibitor are Mer-29 and AY9944. 3,3-Dimethylglutarimide, 3,3-dimethylglutaric acid, 2,2*-di­ me thy Iglufcaric acid, 2,2-dimethyIglutaric acid, 2,2*-dimethylglutaric anhydride, 3,3-dimethylglutaric anhydride, 3-ethyl-3-methylglutarimide, 2-phenyIglutaric anhydride and 3-ethyl-3-methyIglutaric anhydride were tested. Since all attempts to effect cholesterol synthesis in a rat homogenate failed, the derivatives were,examined in vivo. None of these : 14 compounds effectively lowered the incorporation of Na-X-C acetate into cholesterol in the in vivo studies.