On the effect of 2-deuterium- and 2-methyl-eicosapentaenoic acid derivatives on triglycerides, peroxisomal beta-oxidation and platelet aggregation in rats.
A series of 2-substituted eicosapentaenoic acid (EPA) derivatives (as ethyl esters) have been synthesized and evaluated as hypolipidemic and antithrombotic agents in feeding experiments in rats. Repeated administration of purified 2-methyl-eicosapentaenoic acid and its deuterium analogues (all as ethyl esters) to rats resulted in a decrease in plasma triglycerides and high density lipoprotein cholesterol. The 2-methyl-EPA analogues were, apparently, four times more potent than EPA in inducing the triglyceride lowering effect. The 2-deuterium-2-methyl-EPA decreased plasma cholesterol level to approximately 40%. A moderate enlargement of the liver was observed in 2-methyl-EPA treated rats. This was accompanied with an acute reduction in the liver content of triglycerides and a stimulation of peroxisomal beta-oxidation and fatty acyl-CoA oxidase activity. The results suggest that the triglyceride-lowering effect of 2-methyl-EPA may be due to a reduced supply of fatty acids for hepatic triglyceride biosynthesis because of increased fatty acid 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- and 2-deuterium-2-methyl EPA produced a biphasic effect, i.e. potentiation and inhibition at low (250 mg/day kg body weight) and higher doses (600-1300 mg/day kg body weight), respectively. A23187-induced platelet aggregation was affected in a similar way by feeding the 2-substituted EPA derivatives, except that 2-deuterium-2-methyl EPA had no effect relative to EPA itself and that the inhibition was far greater than that for ADP-induced aggregation (approximately 100% inhibition with 600 mg 2-methyl-EPA/day kg body weight). The ranking order of the EPA-derivatives to affect platelet aggregation and to cause hypolipidemia was different, suggesting different mechanisms. Our observations suggest that the effects of the EPA derivatives on platelet aggregation could be related to the degree of bulkiness around C2 and that an asymmetric substitution at C2 caused inhibition of platelet aggregation while a symmetric substitution did not. It is suggested that the bulky, asymmetric derivatives inhibit platelet aggregation by altering platelet membrane phospholipid packing.
Willumsen
N
N
Department of Clinical Biology, Division of Biochemistry, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway.
Vaagenes
H
H
Holmsen
H
H
Berge
R K
RK
D000818:Animals; D001835:Body Weight; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size; D010084:Oxidation-Reduction; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D008076:Cholesterol, HDL; D004041:Dietary Fats; D010975:Platelet Aggregation Inhibitors; D014280:Triglycerides; D015118:Eicosapentaenoic Acid