ON THE EFFECT OF 2-DEUTERIUM-2-METHYL-EICOSAPENTAENOIC AND 2-METHYL-EICOSAPENTAENOIC ACID-DERIVATIVES ON TRIGLYCERIDES, PEROXISOMAL BETA-OXIDATION AND PLATELET-AGGREGATION IN RATS

A series of 2-substituted eicosapentaenoic acid (EFA) derivatives (as ethyl esters) have been synthesized and evaluated as hypolipidemic and antithrombotic agents in feeding experiments in rats. Repeated admini stration of purified 2-methyl-eicosapentaenoic acid and its deuterium analogues (all as ethyl esters) to rats resulted in a decrease in plas ma triglycerides and high density lipoprotein cholesterol. The 2-methy l-EPA analogues were, apparently, four times more potent than EPA in i nducing the triglyceride lowering effect, The 2-deuterium-2-methyl-EPA decreased plasma cholesterol level to similar to 40%. A moderate enla rgement of the liver was observed in 2-methyl-EPA treated rats. This w as accompanied with an acute reduction in the liver content of triglyc erides and a stimulation of peroxisomal beta-oxidation and fatty acyl- CoA oxidase activity, The results suggest that the triglyceride-loweri ng effect of 2-methyl-EPA may be due to a reduced supply of fatty acid s for hepatic triglyceride biosynthesis because of increased fatty aci d oxidation. Platelet aggregation with ADP and A23187 was performed ex vivo in platelet-rich plasma, after administration of different doses of the EPA-derivatives for five days. EPA and 2,2-dideuterium EPA had no effect on ADP-induced aggregation, while 2-deuterium-, 2-methyl- a nd 2-deuterium-2-methyl EPA produced a biphasic effect, i.e. potentiat ion and inhibition at low (250 mg/day/kg body weight) and higher doses (600-1300 mg/day/kg body weight), respectively. A23187-induced platel et aggregation was affected in a similar way by feeding the 2-substitu ted EPA derivatives, except that 2-deuterium-2-methyl EPA had no effec t relative to EPA itself and that the inhibition was far greater than that for ADP-induced aggregation (similar to 100% inhibition with 600 mg 2-methyl-EPA/day kg body weight), The ranking order of the EPA-deri vatives to affect platelet aggregation and to cause hypolipidemia was different, suggesting different mechanisms. Our observations suggest t hat the effects of the EPA derivatives on platelet aggregation could b e related to the degree of bulkiness around C-2 and that an asymmetric substitution at C-2 caused inhibition of platelet aggregation while a symmetric substitution did not. It is suggested that the bulky, asymm etric derivatives inhibit platelet aggregation by altering platelet me mbrane phospholipid packing. (C) 1998 Elsevier Science B.V.