Alkylthioacetic acids (3-thia fatty acids) as non-beta-oxidizable fatty acid analogues: a new group of hypolipidemic drugs. III. Dissociation of cholesterol- and triglyceride-lowering effects and the induction of peroxisomal beta-oxidation.
Previous work in this laboratory indicated that sulfur-substituted fatty acid analogues, 1.10-bis(carboxymethylthio)decane and alkylthioacetic acid, both non-beta-oxidizable compounds, and the beta-oxidizable alkylthiopropionic acid (1) caused, to different extents, dose-related hepatomegaly and proliferation of peroxisomes and enhanced peroxisomal fatty acid beta-oxidation. In the present study, treatment of normolipidemic rats with alkylthioacetic acid resulted in a dose- and 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 affected peroxisomal beta-oxidation 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 dose- and time-related studies of the two compounds, data indicate that the hypotriglyceridemia and hypocholesterolemia were dissociated from induction of peroxisomal beta-oxidation and peroxisome proliferation. Palmitic acid and hexadecanedioic acid, both beta-oxidizable fatty acids, only marginally affected the serum and liver parameters. The beta-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.
Aarsland
A
A
Laboratory of Clinical Biochemistry, University of Bergen, Norway.
Aarsaether
N
N
Bremer
J
J
Berge
R K
RK
D000818:Animals; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
D003998:Dicarboxylic Acids; D005227:Fatty Acids; D010169:Palmitic Acids; D011422:Propionates; D013438:Sulfhydryl Compounds; D013440:Sulfides; D014280:Triglycerides; C062077:1-(carboxyethylthio)tetradecane; D019308:Palmitic Acid; C062079:1,10-bis(carboxymethylthiodecane); C012346:hexadecanedioic acid; D002784:Cholesterol