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Reversal by triton WR-1339 of ethynyloestradiol-induced hepatic cholesterol esterification.

ABSTRACT: RATS TREATED WITH ETHYNYLOESTRADIOL HAVE MARKED HYPOLIPIDAEMIA: serum cholesterol is decreased to 5%, triacylglycerol to 10% and phospholipid to 70% of control concentrations. Loss of serum cholesterol follows an exponential decay, with a half-life of 1.13+/-0.09 days. After 4 days of treatment, serum cholesterol concentrations remain relatively constant (ranging from 1 to 20mg/100ml) for at least 30 days. There is a concomitant 20-fold decrease in the d<1.21 fraction of serum proteins and a similar decrease in serum apolipoproteins as measured by sodium dodecyl sulphate/10%-polyacrylamide-gel electrophoresis. The activity of hepatic microsomal acyl-CoA-cholesterol O-acetyltransferase (EC 2.3.1.26) was significantly increased by ethynyloestradiol treatment (P<0.05). This activation caused hepatic cholesteryl esters containing mainly C(18:1) fatty acids to increase linearly as serum cholesterol concentrations decreased (r=0.9675, P<0.001). Triton WR-1339, a non-ionic detergent that inhibits lipoprotein catabolism, was used to estimate hepatic lipid secretion by measuring the increment in serum lipids after its administration. At 15h after Triton WR-1339 administration, serum cholesterol concentrations were increased equally in both control and ethynyloestradiol-treated rats. In contrast, the increment of serum triacylglycerol of treated rats was 40% of that found in control rats, indicating that ethynyloestradiol inhibits hepatic triacylglycerol secretion. Triton WR-1339 inhibited the oestrogen activation of hepatic microsomal acyl-CoA-cholesterol O-acyltransferase and restored hepatic cholesteryl ester concentrations to normal values. These data suggest that ethynyloestradiol and its pharmacological ;antagonist' Triton WR-1339 alter hepatic triacylglycerol secretion via a mechanism associated with changes in hepatic cholesterol esterification.

SUBMITTER: Davis RA

PROVIDER: S-EPMC1185883 | biostudies-other | 1978 Jul

REPOSITORIES: biostudies-other

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Project description:The hypolipidemic effect of furan carboxamide derivatives was investigated using the Triton WR-1339 rat model. Nineteen compounds were synthesized, including furan-2-carboxamides of benzophenones and acetophenones (a(1-4)), anilines and amine derivatives (a(5-9)), picolinic-2-carboxamide derivatives of benzophenones and acetophenone (a(10-12)) and furan-2-carboxylate esters of benzophenones and acetophenones, substituted phenols and alcohols (b(1-7)). All the necessary steps were taken to synthesize, purify, and characterize these compounds. They were synthesized by reacting acyl chlorides of the heterocycles with their corresponding amines in the presence of pyridine and tert-butyl acetate. While the conventional heating method yielded acceptable yields for some of the reactions under reflux, the microwave synthesis reactor achieved significantly higher yields for others. Rats with hyperlipidemia were induced with Triton WR-1339 and then subjected to in vivo testing via an intraperitoneal injection of 200 mg kg-1 Triton WR-1339. The model was tested using an oral dose of bezafibrate (100 mg kg-1). After 7 hours of treatment with Triton, the new derivatives represented by compounds a(1-2), a(4-5), a7, and a(10-12) showed significant activity against the complete lipid profile, including a decrease in triglyceride, total cholesterol, and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol plasma levels. At 20 mg kg-1 dose, these compounds were superior to other lipid-lowering agents in reducing triglyceride levels and slightly increased high-density lipoprotein cholesterol levels. These results indicate a mutual mechanism of action of novel compounds with fibrates, where they have a marked effect on triglyceride and high-density lipoprotein cholesterol levels; for example, a5 causes a significant reduction (p 0.0001) of triglyceride levels by 86%, and a remarkable increase (p 0.0001) in high-density lipoprotein cholesterol plasma levels by 65% as compared to hyperlipidemic rats.

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Reversal by triton WR-1339 of ethynyloestradiol-induced hepatic cholesterol esterification.

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