Willumsen N, Vaagenes H, Holmsen H, Berge R K
Department of Clinical Biology, Division of Biochemistry, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway.
Biochim Biophys Acta. 1998 Mar 2;1369(2):193-203. doi: 10.1016/s0005-2736(97)00211-3.
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.
已合成了一系列2-取代的二十碳五烯酸（EPA）衍生物（作为乙酯），并在大鼠喂养实验中作为降血脂和抗血栓形成剂进行了评估。给大鼠反复施用纯化的2-甲基-二十碳五烯酸及其氘代类似物（均作为乙酯）导致血浆甘油三酯和高密度脂蛋白胆固醇降低。显然，2-甲基-EPA类似物在诱导甘油三酯降低作用方面的效力比EPA高四倍。2-氘代-2-甲基-EPA使血浆胆固醇水平降低至约40%。在2-甲基-EPA处理的大鼠中观察到肝脏适度肿大。这伴随着肝脏甘油三酯含量的急剧降低以及过氧化物酶体β-氧化和脂肪酰辅酶A氧化酶活性的刺激。结果表明，2-甲基-EPA的降甘油三酯作用可能是由于脂肪酸氧化增加，导致用于肝脏甘油三酯生物合成的脂肪酸供应减少。在给予不同剂量的EPA衍生物五天后，在富含血小板的血浆中离体进行了用ADP和A23187诱导的血小板聚集实验。EPA和2,2-二氘代-EPA对ADP诱导的聚集没有影响，而2-氘代-、2-甲基-和2-氘代-2-甲基-EPA产生了双相作用，即在低剂量（250毫克/天·千克体重）时增强，在高剂量（600 - 1300毫克/天·千克体重）时抑制。喂食2-取代的EPA衍生物对A23187诱导的血小板聚集的影响方式类似，不同之处在于2-氘代-2-甲基-EPA相对于EPA本身没有影响，并且其抑制作用远大于对ADP诱导的聚集的抑制作用（用600毫克2-甲基-EPA/天·千克体重时约100%抑制）。EPA衍生物影响血小板聚集和引起降血脂的排序不同，表明机制不同。我们的观察结果表明，EPA衍生物对血小板聚集的影响可能与C2周围的体积大小有关，并且C2处的不对称取代导致血小板聚集受到抑制，而对称取代则不会。有人提出，庞大的不对称衍生物通过改变血小板膜磷脂堆积来抑制血小板聚集。
