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Search for other papers by N. DESHPANDE in
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SUMMARY
Factors controlling the synthesis of androstenedione in the human adrenal gland were investigated in a kinetic study of the enzymes catalysing the conversion of 17α-hydroxyprogesterone and dehydroepiandrosterone to the hormone. Both reactions are associated with the microsomal fraction of the adrenal cell. 17α-Hydroxyprogesterone is converted to androstenedione by a NADPH-dependent 17-desmolase whereas there is an obligatory requirement for NAD+ for the conversion of dehydroepiandrosterone to the hormone. None of the other cofactors investigated inhibited or enhanced the enzymic conversions.
The side-chain cleavage of 17α-hydroxyprogesterone was competitively inhibited by the precursors of the substrate, pregnenolone, progesterone and 17α-hydroxypregnenolone. Other C19 or C18 compounds known to be synthesized by the human adrenal gland were found to be ineffective in modifying the enzyme action. The conversion of dehydroepiandrosterone to androstenedione was non-competitively inhibited by oestrone and oestradiol-17β. No C21 compounds were found to affect the reaction. 5α-Dihydrotestosterone (17β-hydroxy-5α-androstan-3-one) inhibited both enzymic conversions competitively but the inhibition constants observed were so high that it is unlikely that this finding has any relevance to the control of androstenedione synthesis in vitro.
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Department of Clinical Endocrinology, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, WC2A 3PX
(Received 2 August 1974)
Evidence has often been presented for the existence of multiple 3β-hydroxysteroid dehydrogenase/3-oxosteroid isomerase systems on the basis of preferential conversion of only one of the several possible substrates of these enzymes (Weliky & Engel, 1963; Neville, Webb & Symington, 1969). Three, or possibly four, substrate-specific isomerases have been demonstrated in mammalian adrenal glands (Alfsen, Baulieu & Claquin, 1965; also see Neville et al. 1969). More recently the 3β-hydroxysteroid dehydrogenase/isomerase system of sheep adrenal cortex microsomes has been isolated; purification of the enzymes by ion exchange chromatography revealed no separation of activities towards dehydroepiandrosterone (DHA) and pregnenolone (Ford & Engel, 1974). However, similar information on the human adrenal gland is lacking and since this enzyme system(s) might be important in the production of cortisol and androgens, an attempt has been made to investigate
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The effects of administration of testosterone propionate on the activities of seven of the enzymes of carbohydrate metabolism in normal rat mammary glands were investigated and the validity of the results was confirmed by simultaneous injection of the hormone and cyproterone acetate. The administration of the androgen increased the activities of phosphofructokinase (PFK), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH) and lactate dehydrogenase (LDH) in glands from both intact and from ovariectomized and adrenalectomized animals. Administration of cyproterone acetate alone resulted in a significant reduction in the activities of PFK and G6PDH and when given together with the androgen it inhibited increases in the activities of PFK, G6PDH, 6PGDH and LDH induced by testosterone. It was concluded that these results did not explain the known inhibitory effects of the androgen on normal mammary gland growth and function.
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The possible involvement of opioids in carbohydrate metabolism in rat mammary glands was investigated by studying the effects of administration of morphine and naloxone on six enzymes. Morphine inhibited phosphofructokinase (PFK) and stimulated phosphohexose isomerase (PHI) activities. Naloxone treatment alone, to both intact and ovariectomized/adrenalectomized animals, resulted in stimulation of PFK and inhibition of PHI activities. A combined dose of morphine and naloxone to intact animals showed that the opiate antagonist was able to reverse the morphine-induced changes. Evidence is presented to show that the changes observed in PHI activity may be the result of the indirect action of opioids on luteinizing hormone releasing hormone. However, the changes observed in PFK activity might be the result of direct action of opioids. Failure to observe changes in enzyme activities after naloxone treatment of hypophysectomized animals suggests the opiate antagonist might be acting on the pituitary gland to block the release of endorphins.
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Abstract
The influence of the type of dietary fat on the effects of thyroid hormones was investigated in mice. Hyperthyroidism was achieved by providing thyroid hormones (T3 and T4) in the drinking water. Both hyperthyroid and euthyroid mice (Mus musculus) were fed isoenergetic diets containing 18% (w/w) total lipid but differing in fatty acid composition. Diets were either low in the polyunsaturated linoleic acid (18:2, ω6) and high in saturated fatty acids (SFAs) or low in saturated fats and high in the polyunsaturated fatty acid (PUFA), linoleic acid. Treatments were maintained for 21–22 days. Plasma thyroid hormone levels, standard metabolic rate (SMR), changes in body mass, specific activities of malic enzyme (ME), Na-K-ATPase and glycerolphosphate dehydrogenase (GPDH) of the liver were measured. Fatty acid composition of the liver phospholipids was also determined. Levels of T3 (15–17 nm) and T4 (250–255 nm) were significantly higher in the respective hyperthyroid groups. There was no significant influence of the diet on hormone levels. Hyperthyroidism increased the SMR 37–44% above the euthyroid levels. A significant body weight loss of 14–18% was observed in hyperthyroid mice on the PUFA diet but not in those on the SFA diet. PUFA diet significantly reduced the activity of ME but had no effect on Na-K-ATPase or GPDH activity. Activities of Na-K-ATPase and GPDH were significantly elevated in all hyperthyroid groups. Mice on T4 and PUFA diet showed a highly significant 399% increase in GPDH activity above the euthyroid level. The overall degree of unsaturation of the fatty acids in the liver phospholipids was comparable in all groups. Dietary treatment substantially changed liver membrane fatty acid composition whilst hyperthyroidism resulted in only small changes. The only parameters to show an interaction between dietary fat profile and hyperthyroidism were ME activity, changes in body mass and liver phospholipid fatty acid composition.
Journal of Endocrinology (1995) 144, 431–439
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SUMMARY
The control of dehydroepiandrosterone (DHA) synthesis in the human adrenal gland was studied by investigating the biosynthesis of its immediate precursor, 17-hydroxypregnenolone (3β,17α-dihydroxy-pregn-5-en-20-one) and the side-chain cleavage. Both conversions take place in the microsomal fraction and there is an obligatory requirement for the co-factor, reduced nicotinamide adenine dinucleotide phosphate (NADPH). Under optimal conditions, 17-hydroxylation is controlled only by the availability of the substrate and the co-factor. By using the same kinetic approach it was observed that the synthesis of DHA is controlled by the availability of substrate and co-factor. However, the reaction was inhibited by the oxidized form (NADP+) and when the ratio of NADP+:NADPH reached 1, the maximum velocity was halved.
Two major metabolites of 17-hydroxypregnenolone, namely DHA and 17-hydroxyprogesterone, are non-competitive inhibitors of the reaction. The inhibition constants are of the magnitude of the tissue concentration of these steroids in the adrenal gland which suggests that non-competitive inhibition takes place in vivo.
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SUMMARY
An in-situ continuous infusion technique was used to study the biogenesis of androgens and cortisol in the guinea-pig adrenal gland after the infusion of 3H- and 14C-labelled precursors of these compounds. Pregnenolone was converted to 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone and cortisol. The results of infusion of a combined dose of [3H]17α-hydroxypregnenolone and [14C]progesterone indicated that the major pathway to cortisol is via 17α-hydroxypregnenolone. No conclusive proof could be obtained regarding synthesis of dehydroepiandrosterone or androst-4-ene-3,17-dione. The only androgen detected in the guinea-pig adrenal venous blood was 11β-hydroxyandrost-4-ene-3,17-dione. The major and minor biosynthetic pathways involved in the synthesis of these hormones are discussed.
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SUMMARY
(1) Total 17-hydroxycorticosteroids (17-OHCS) and 17-oxosteroids have been determined simultaneously in plasma from 76 normal men.
(3) The 17-OHCS are positively correlated with age and negatively with weight. The 17-oxosteroids are negatively correlated with age.
(3) The age-adjusted mean 17-OHCS levels are identical in men and women but the age relationship differs significantly. Conversely, the slopes of the regressions of 17-oxosteroids on age are the same but the adjusted mean level is higher in men than in women.
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SUMMARY
A simple method for the simultaneous estimation of 17-hydroxycorticosteroids and 17-oxosteroids in human plasma is described. It involves extraction of free corticosteroids, hydrolysis of glucuronosides with β-glucuronidase and solvolysis of sulphates, chromatography on silica gel and colorimetry using microcells. Recoveries of added steroids, using appropriate conjugated compounds were over 80%.
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SUMMARY
The method of Deshpande & Bulbrook (1964) for the determination of total 17-oxosteroids and 17-hydroxycorticosteroids (17-OHCS) in blood has been employed in a study of fifty-two normal women of different ages. The results show that there is a significant correlation between age and the plasma levels of 17-oxosteroids and 17-OHCS. Contrary to similar studies on urines, no other parameter gave a significant correlation. Factors which might control the relative amounts of plasma 17-oxosteroids and 17-OHCS are discussed.
