Effects of ethynyloestradiol on the metabolism of [1-14C]-oleate by perfused livers and hepatocytes from female rats

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Abstract
Normal female rats were given 15 .mu.g of ethynylestradiol/kg body wt for 14 days and were killed on day 15 after starvation for 12-14h. The livers were isolated and were perfused with a medium containing washed bovine erythrocytes, bovine serum albumin, glucose and [1-14C]oleic acid; 414 .mu.mol of oleate were infused/h during a 3 h experimental period. The output of bile and the flow of perfusate/g of liver were decreased in livers from animals pretreated with ethynylestradiol, whereas the liver weight was increased slightly. The rates of uptake and of utilization of [1-14C]oleate were measured when the concentration of unesterified fatty acid in the perfusate plasma was constant. The uptake of unesterified fatty acid was unaffected by pretreatment of the animal with estrogen; the rate of incorporation of [1-14C]oleate into hepatic and perfusate triacylglycerol was stimulated, whereas the rate of conversion into ketone bodies was impaired by treatment of the rat with ethynylestradiol. Pretreatment of the rat with ethynylestradiol increased the output of very-low-density lipoprotein triacylglycerol, cholesterol, phospholipid and protein. The production of 14CO2 and the incorporation of radioactivity into phospholipid, cholesteryl ester and diacylglycerol was unaffected by treatment with the steroid. The net output of glucose by livers from estrogen-treated rats was impaired despite the apparent increased quantities of glycogen in the liver. The overall effect of pretreatment with estrogen on hepatic metabolism of fatty acids is the channeling of [1-14C]oleate into synthesis and increased output of triacylglycerol as a moiety of the very-low-density lipoprotein, whereas ketogenesis is decreased. The effect of ethynylestradiol on the liver is apparently independent of the nutritional state of the animal from which the liver was obtained. It is pertinent that hepatocytes prepared from livers of fed rats that had been treated with ethynylestradiol produced fewer ketone bodies and secreted more triacylglycerol than did hepatocytes prepared from control animals. In these respects, the effects of the steroid were similar in livers from fed or starved (12-14 h) rats. Estrogens may possibly inhibit hepatic oxidation of fatty acid, making more fatty acid available for the synthesis of triacylglycerol; they may also stimulate the biosynthesis of triacylglycerol or be active on both metabolic pathways. Hypertriglyceridaemia is often an undesirable side effect of therapy with oral contraceptives containing estrogens. The increase in serum triacylglycerol was observed to be proportional to the estrogen content of the oral contraceptive drug. Subsequently, several laboratories reported that the administration of estrogen component alone to humans, rats and birds resulted in hypertriglyceridemia.

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