Hypolipidemic effect and enhancement of peroxisomal beta-oxidation in the liver of rats by sodium-(E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl propenoate (OKY-1581), a potent inhibitor of TxA2 synthetase.
The effects of sodium-(E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl propenoate (OKY-1581) and (E)-3-(4-(imidazolylmethyl)phenyl)-2-propenoic acid (OKY-046), potent inhibitors to thromboxane A2 synthetase, on peroxisomal beta-oxidation and on lipid levels of liver and serum in the rat were studied. When the animals were administered with OKY-1581 at the dose levels of 100 and 500 mg/kg body weight for 2 weeks, the activity of peroxisomal beta-oxidation increased 2.2- and 6.3-fold respectively. Catalase activity increased 1.3-fold, whereas D-amino acid oxidase (DAAO) and urate oxidase activities did not change. Carnitine acetyltransferase and carnitine palmitoyltransferase activities also increased 2.2- - 4.1-fold and 2.7- - 4.2-fold respectively. These changes of the enzymes related to lipid metabolism were also confirmed by the results of a cell fractionation study. Moreover, the induction of peroxisome proliferation-associated polypeptide having a molecular weight of 80000, which is a bifunctional enzyme in the peroxisomal beta-oxidation system was also observed electrophoretically in the light mitochondrial fraction of the liver of OKY-1581-treated rat. The contents of triglyceride and cholesterol in the serum decreased. These results indicated that the action of OKY-1581 in enhancing hepatic peroxisomal-oxidation is similar to that of a potent hypolipidemic peroxisome proliferator such as clofibrate. On the other hand, differing from OKY-1581, OKY-046 at the dose level of 500 mg/kg for 2 weeks showed no effect on serum and liver lipid levels and on the activities of the peroxisomal enzymes, including a cyanide-insensitive fatty acyl-CoA oxidizing system and carnitine acetyl transferase.
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D008830:Microbodies / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D000960:Hypolipidemic Agents; D008689:Methacrylates; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D013930:Thromboxane-A Synthase; D002994:Clofibrate; C034364:ozagrel