CLOFIBRATE AND OTHER PEROXISOMAL PROLIFERATING AGENTS RELATIVELY SPECIFICALLY INHIBIT SYNTHESIS OF ETHANOLAMINE PHOSPHOGLYCERIDES IN CULTURED HUMAN FIBROBLASTS

Effects of several classes of peroxisomal proliferators on peroxisomal functions, hepatomegaly, hepatocarcinogenesis and lipid metabolism ha ve been extensively investigated in rodents. Less is known about influ ences of these agents, some used as hypolipidemic drugs, on various me tabolic parameters in humans. We examined effects of clofibrate, di(2- ethyl-hexyl)phthalate (DEHP) and pirinixic acid (WY-14,643) on phospho lipid metabolism in human fibroblasts in culture. Clofibrate inhibited incorporation of [1-C-14]hexadecanol and [1-C-14]linolenic acid into ethanolamine phosphoglycerides in a time- and concentration-dependent manner; labeling of plasmalogens and non-plasmalogen ethanolamine phos phoglycerides was reduced by 40-80% compared to a generalized 10-30% i nhibition of labeling of other phospholipids, including phosphatidylch oline. In pulse and pulse-chase experiments, selective inhibition of i ncorporation of [1,2-C-14]ethanolamine, compared to [methyl-H-3]cholin e, confirmed relative specificity of inhibition of ethanolamine phosph oglycerides. Similar concentration dependence and specificity for inhi bition of phospholipid turnover was observed for DEHP and WY-14,643, i n both control and mutant (Zellweger and adrenoleukodystrophy) fibrobl asts, in the absence of major effects on peroxisomal markers. These ob servations that peroxisomal proliferators specifically inhibit ethanol amine phosphoglyceride turnover in human fibroblasts should be conside red when assessing the efficacy and safety of such agents as hypolipid emic drugs or when evaluating mechanisms of proliferator action at the cellular level.