Thorne P C, Byers D M, Palmer F B, Cook H W
Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
Biochim Biophys Acta. 1994 Sep 15;1214(2):161-70. doi: 10.1016/0005-2760(94)90040-x.
Effects of several classes of peroxisomal proliferators on peroxisomal functions, hepatomegaly, hepatocarcinogenesis and lipid metabolism have been extensively investigated in rodents. Less is known about influences of these agents, some used as hypolipidemic drugs, on various metabolic parameters in humans. We examined effects of clofibrate, di(2-ethyl-hexyl)phthalate (DEHP) and pirinixic acid (WY-14,643) on phospholipid metabolism in human fibroblasts in culture. Clofibrate inhibited incorporation of [1-14C]hexadecanol and [1-14C]linolenic acid into ethanolamine phosphoglycerides in a time- and concentration-dependent manner; labeling of plasmalogens and non-plasmalogen ethanolamine phosphoglycerides was reduced by 40-80% compared to a generalized 10-30% inhibition of labeling of other phospholipids, including phosphatidylcholine. In pulse and pulse-chase experiments, selective inhibition of incorporation of [1,2-14C]ethanolamine, compared to [methyl-3H]choline, confirmed relative specificity of inhibition of ethanolamine phosphoglycerides. Similar concentration dependence and specificity for inhibition of phospholipid turnover was observed for DEHP and WY-14,643, in both control and mutant (Zellweger and adrenoleukodystrophy) fibroblasts, in the absence of major effects on peroxisomal markers. These observations that peroxisomal proliferators specifically inhibit ethanolamine phosphoglyceride turnover in human fibroblasts should be considered when assessing the efficacy and safety of such agents as hypolipidemic drugs or when evaluating mechanisms of proliferator action at the cellular level.
几类过氧化物酶体增殖剂对啮齿动物过氧化物酶体功能、肝肿大、肝癌发生和脂质代谢的影响已得到广泛研究。关于这些药物（其中一些用作降血脂药物）对人类各种代谢参数的影响，人们了解较少。我们研究了氯贝丁酯、邻苯二甲酸二（2-乙基己基）酯（DEHP）和吡利昔酸（WY-14,643）对培养的人成纤维细胞磷脂代谢的影响。氯贝丁酯以时间和浓度依赖性方式抑制[1-14C]十六醇和[1-14C]亚麻酸掺入乙醇胺磷酸甘油酯；与包括磷脂酰胆碱在内的其他磷脂标记的普遍10-30%抑制相比，缩醛磷脂和非缩醛磷脂乙醇胺磷酸甘油酯的标记减少了40-80%。在脉冲和脉冲追踪实验中，与[甲基-3H]胆碱相比，[1,2-14C]乙醇胺掺入的选择性抑制证实了乙醇胺磷酸甘油酯抑制的相对特异性。在对照和成纤维细胞突变体（泽尔韦格综合征和肾上腺脑白质营养不良）中，DEHP和WY-14,643对磷脂周转的抑制具有相似的浓度依赖性和特异性，且对过氧化物酶体标记物无主要影响。在评估此类降血脂药物的疗效和安全性或在细胞水平评估增殖剂作用机制时，应考虑过氧化物酶体增殖剂特异性抑制人成纤维细胞中乙醇胺磷酸甘油酯周转的这些观察结果。
