Alkylthioacetic acids (3-thia fatty acids) as non-P-oxidizable fatty acid analogues: a new group of hypolipidemic drugs. Ill. Dissociation of cholesterol= and triglyceride-lowering effects and the induction of peroxisomal @oxidation

Previous work in this laboratory indicated that sulfursubstituted fatty acid analogues, 1 . lO-bis(carboxymethylthio)decane and alkylthioacetic acid, both non-@-oxidizable compounds, and the @-oxidizable alkylthiopropionic acid (1) caused, to different extents, dase-related hepatomegaly and proliferation of pemxi"es and enhanced pervxisomal fatty acid 8-oxidation. In the present study, treatment of nonnolipidemic rats with alkylthioacetic acid resulted in a doseand time-dependent decrease in serum cholesterol and serum and liver triglycerides to an extent comparable to that of the 3-thiadicarboxylic acid. At hypolipidemic doses, alkylthioacetic acid caused no hepatomegaly, did not significantly alter peroxisome morphology, and only marginally d&ed peroxisomal @-axidation activity. Only at the highest, nonpharmacological doses of alkylthioacetic acid were these hepatic parameters increased, although to a lesser extent than by the 3-thiadicarboxylic acid. Hence, on the basis of doseand time-related studies of the two compounds, data indicate that the hypotriglyceridemia and hypocholesterolemia were dissociated from induction of peroxisomal @oxidation and peroxisome proliieration. Palmitic acid and hexadecanedioic acid, both @-oxidizable fatty acids, only marginally affected the serum and liver parameters. (M The @-oxidizable fatty acid analogue, alkylthiopropionic acid lowered the serum triglycerides in normolipidemic rats. In contrast to the 3-thiadicarboxylic acid and alkylthioacetic acid, alkylthiopropionic acid treatment at hypolipidemic doses caused accumulation of triglycerides in the liver.-Aanlanci, A., N. Aanacthcr, J. B-er, and R. K. Berge. Alkylthioacetic acids (3-thia fatty acids) as non-8-oxidizable fatty acid analogues: a new group of hypolipidemic drugs. 111. Dissociation of cholesteroland triglyceride-lawering effects and the induction of pemxisomal @-oxidation. J Lipid Res. 1989. 3