Ergosteroids: induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone.

Abstract

Dehydroepiandrosterone (DHEA), an intermediate in the biosynthesis of testosterone and estrogens, exerts several physiological effects not involving the sex hormones. When fed to rats it induces the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in their livers. Animals and humans, and their excised tissues, are known to hydroxylate DHEA at several positions and to interconvert 7a-hydroxy-DHEA, 7,8-hydroxy-DHEA, 7-oxo-DHEA, and the corresponding derivatives of androst-5-enediol. We report here that these 7-oxygenated derivatives are active inducers of these thermogenic enzymes in rats and that the 7-oxo derivatives are more active than the parent steroids. We postulate that the 7cr-hydroxy and 7-oxo derivatives are on a metabolic pathway from DHEA to more active steroid hormones. These 7-oxo steroids have potential as therapeutic agents because of their increased activity and because they are not convertible to either testosterone or estrogens.We wish to report the biological activity of some known and some newly discovered steroids structurally related to dehydroepiandrosterone (androst-5-ene-313-ol-17-one; DHEA). DHEA is produced in the adrenals and brain and is the most abundant steroid in the blood of adult humans; it reaches a maximum concentration at 20-25 years of age and declines thereafter. It circulates mainly as the sulfate ester but the ester and free steroid are metabolically interconverted (1, 2). DHEA is an intermediate in the metabolic conversion of cholesterol to testosterone and estrogens and it also exerts several physiological effects independent of the sex hormones. In relatively large doses, it causes weight loss in genetically obese (3) and normal (4) animals without affecting food intake; it depresses blood cholesterol levels in men (5), rats (6), and dogs (7); it decreases blood sugar concentration in diabetic mice (8); it enhances resistance of mice to viral infections (9, 10); it reduces the incidence of spontaneous (11, 12) and carcinogen-induced (13) tumors in mice; and it improves memory in aged mice (14). Body weight responses in humans treated with DHEA are questionable (5,(15)(16)(17)(18)(19).The diversity of the responses to DHEA and the large doses (-0.5% of the diet for animals) required to elicit most of them led to the postulate that DHEA might be the precursor of steroid hormones other than the sex hormones and that these metabolites might be active in smaller doses and might display specificity for one, or only a few, of the effects described above.We therefore synthesized known and possible metabolites of DHEA in the hope of finding compounds with greater biological activity. Another objective was to find metabolites of DHEA that retained the activities of the parent except for the ability to form androgens and estrogens. DHEA should not be used by women for extended periods because it increases their circulating testosterone and dihydrotestosterone manyfoldThe publication costs of this article were defrayed in p...

Dehydroepiandrosterone treatment attenuates oestrogen-induced pituitary hyperplasia

“…It has been proposed that this action involves inhibition of hepatic lipogenesis as a result of a reduction in NADPH production (Parente & Berdanier 1993). Besides, DHEA or its 7-oxygenated derivatives can enhance heat production by inducing the liver thermogenic enzymes glycerol-3-phosphate dehydrogenase and the malic enzyme (Shepherd & Cleary 1984, Lardy et al 1995. The effect of DHEA on food intake is not clear (Cleary 1991, Richards et al 2000, and in our present experiments we did not find changes in serum leptin levels in DHEA-treated rats.…”

7α-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system

“…The formation of 7␣-hydroxylated neurosteroids, such as 7␣-hydroxypregnenolone and 7␣-hydroxydehydroepiandrosterone, has been observed only in the brain of mammals, such as laboratory rodents and humans (21)(22)(23)(24). In mammals, 7␣-hydroxylation of dehydroepiandrosterone may be part of a metabolic pathway to more potent derivatives (25), and 7␣-hydroxydehydroepiandrosterone is more active than dehydroepiandrosterone in preventing hypoxic cell death of neurons in vitro (26). In contrast to these mammalian studies, no investigation has been published on the formation of 7␣-hydroxypregnenolone in nonmammalian vertebrates, to our knowledge.…”

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

“…Mitochondrial glycerophosphate dehydrogenase (mGPDH), a member of the glycerophosphate shuttle, is known to be induced by thyroid hormone (Lee and Lardy 1965), dehydroepiandrosterone (Su and Lardy 1991;Lardy et al 1995), and peroxisome proliferators (Shoemaker and Yamazaki 1991). These may be effective in activating the glycerophosphate shuttle, and in decreasing the cytosolic NADH/NAD ϩ ratio.…”