Inhibition of Hepatic Acetyl Coenzyme by Hypolipidemic Agents*

The effects of two hypolipidemic agents, 2-methyl-2-[p(1,2,3,4-tetrahydro-l-naphthyl)-phenoxy]propionate and ethyl 2-(p-chlorophenyl)-2-methylpropionate, on the activity of a highly purified preparation of acetyl coenxyme A carboxylase, obtained from chicken livers, were studied. Both compounds are inhibitors of acetyl-CoA carboxylase, but they have no inhibitory effect on a number of other enzymes tested, including fatty acid synthetase. The inhibition cannot be prevented by addition of exogenous biotin. Kinetic analysis indicates that the inhibition is competitive for acetyl-CoA and isocitrate and noncompetitive for ATP and bicarbonate for both drugs. Mixed inhibition studies indicate that both drugs act on the same site of the enzyme and that this site is different from the site of inhibition by palmityl-CoA. Some insight into the mechanism of the inhibition is provided by the kinetic analysis, heat inactivation studies, sucrose gradient sedimentation, and Arrhenius plots. The results suggest that the effect of these compounds as lipid-lowering agents may be accounted for by inhibition of acetyl-CoA carboxylase in vivo. From the Research Department, CIBA Pharmaceutical Company, Summit, New Jersey 07901