Drugs affecting the synthesis of glycerides and phospholipids in rat liver. The effects of clofibrate, halofenate, fenfluramine, amphetamine, cinchocaine, chlorpromazine, demethylimipramine, mepyramine and some of their derivatives

Abstract

The effects on glycerolipid synthesis of a series of compounds including many drugs were investigated in cell-free preparations and slices of rat liver. p-Chlorobenzoate, p-chlorophenoxyisobutyrate, halofenate, D-amphetamine, adrenaline, procaine and N-[2-(4-chloro-3-sulphamoylbenzoyloxy)ethyl]norfenfluramine had little inhibitory effect on any of the systems investigated. Two amphiphilic anions, clofenapate and 2-(p-chlorophenyl)-2-(m-trifluoromethylphenoxy)acetate, both inhibited glycerol phosphate acyltransferase and diacylglycerol acyltransferase at approx. 1.6 and 0.7 mm respectively. Clofenapate (1 mm) also inhibited the incorporation of glycerol into lipids by rat liver slices without altering the relative proportions of the different lipids synthesized. The amphilic amines, mepyramine, fenfluramine, norfenfluramine, hydroxyethylnorfenfluramine, N-(2-benzoyloxyethyl)norfenfluramine, cinchocaine, chlorpromazine and demethylimipramine inhibited phosphatidate phosphohydrolase by 50% at concentrations between 0.2 and 0.9 mm. The last four compounds inhibited glycerol phosphate acyltransferase by 50% at concentrations between 1 and 2.6 mm. None of the amines examined appeared to be an effective inhibitor of diacylglycerol acyltransferase. Norfenfluramine, hydroxyethylnorfenfluramine and N-(2-benzoyloxyethyl)norfenfluramine produced less inhibition of glycerol incorporation into total lipids than was observed with equimolar clofenapate. The major effect of these amines in liver slices was to inhibit triacylglycerol and phosphatidylcholine synthesis and to produce a marked accumulation of phosphatidate. The results are discussed in terms of the control of glycerolipid synthesis. They partly explain the observed effects of the various drugs on lipid metabolism. The possible use of these compounds as biochemical tools with which to investigate the reactions of glycerolipid synthesis is considered.

Stimulation of cardiac cardiolipin biosynthesis by PPARα activation

“…Thus, incubation of cells with these compounds could erroneously affect [1, H]glycerol incorporation into various phospholipids. Clofibrate had little effect on the synthesis of glycerides, phospholipids, phosphatidate phosphohydrolase, or DG acyltransferase activities in rat liver slices (34). In agreement with these observations, PA phosphohydrolase activity in rat myoblastic H9c2 cells was unaltered by clofibrate preincubation.…”

The effect of acute and chronic ethanol intake on hepatic glycerolipid biosynthesis in the hamster.

“…Alternatively, the two activities could have different specificities or functions as yet unrecognized. Nevertheless, both supernatant and microsomal phosphatidate phosphohydrolase showed similar increases in activity after ethanol administration, which is consistent with other evidence that phosphatidate phosphohydrolase is important in the regulation of hepatic triglyceride formation during high sugar intake (26,33), fasting (34), hepatectomy (35), obesity (36), diabetes (37), toxin exposure (38,39), and exposure to lipid-lowering agents (21,40). Hence, phosphatidate phosphohydrolase appears to possess characteristics of a ratecontrolling reaction because (a) it regulates a branch point between phospholipid and triglyceride biosynthesis; (b) it has a lower reaction rate in vitro than other enzymes involved in glycerolipid biosynthesis; and (c) it exhibits rapid responses in activity under various physiological and nutritional conditions.…”

Properties of Microsomal and Soluble Diacylglycerol Kinase in Rat Liver

“…Both enzymes could be stored at -20 "C in the presence of 1 mM dithiothreitol for about a week without loss of activity. Microsomal kinase was inhibited 50 % by 1 mM fenfluramine, which is the same concentration range as reported for inhibition of phosphatidate phosphohydrolase [40], but soluble enzyme was much more resistent and was inhibited 40 % by 4 mM fenfluramine.…”