Dietary dehydroepiandrosterone inhibits bone marrow and leukemia cell transplants: role of food restriction.

Dietary dehydroepiandrosterone (DHEA) inhibits the proliferation of syngeneic bone marrow cells (BMC) infused into lethally irradiated mice. Potential mechanisms for suppression of hematopoiesis were evaluated and the findings were as follows: (i) depletion of NK, T, B or macrophage cells failed to reverse suppression by DHEA; (ii) stem cell stimulation by erythropoietin, growth hormone, interleukin-2, Friend leukemia virus, or cyclophosphamide failed to reverse suppression; (iii) supplementation of fatty acids, mevalonate, or deoxyribonucleotides, which are dependent upon glucose-6-phosphate dehydrogenase function, did not enhance BMC growth in mice fed DHEA; (iv) DHEA downstream metabolites 4-androstenedione and 17beta-estradiol, as well as the synthetic steroid, 16alpha-chloroepiandrosterone (but not testosterone or 5-androstene-3beta,17beta-diol), also inhibited BMC growth. Tamoxifen antagonized the effects of 17beta-estradiol but not DHEA; (v) dietary DHEA causes hypothermia, but housing of DHEA-fed mice at 34 degrees C to maintain normal body temperature did not reverse suppression; (vi) DHEA leads to a decrease in food intake in rodents.

Decrease of core body temperature in mice by dehydroepiandrosterone.

Dietary dehydroepiandrosterone (DHEA) reduces food intake in mice, and this response is under genetic control. Moreover, both food restriction and DHEA can prevent or ameliorate certain diseases and mediate other biological effects. Mice fed DHEA (0.

Food restriction-like effects of dietary dehydroepiandrosterone. Hypothalamic neurotransmitters and metabolites in male C57BL/6 and (C57BL/6 x DBA/2)F1 mice.

Dehydroepiandrosterone (DHEA) is a precursor of sex hormones in mammals. Dietary DHEA serves to prevent or inhibit various diseases and also lengthens life spans of animals. Moreover, dietary DHEA inhibits food intake in certain strains of mice.

Food restriction-like effects of dehydroepiandrosterone: decreased lymphocyte numbers and functions with increased apoptosis.

Both dietary dehydroepiandrosterone (DHEA) and food restriction can prevent or modulate the initiation or progression of a number of diseases in rodents and prolong life span. We sought to determine if these interventions have common mechanisms of action in regulating lymphocyte functions and cell numbers. We observed that male C57BL/6 mice receiving DHEA in the diet (0.

Pleotropic effects of dietary DHEA.

We present data pertaining to some of the in vivo effects associated with dietary DHEA administration to mice and rats. Dietary DHEA leads to: (1) decrease in body weight gain; (2) relative increases in liver weight; (3) liver color change; (4) induction of hepatic peroxisomal enzymes; (5) proliferation of hepatic peroxisomes with increased cross-sectional area; (6) decreased hepatic mitochondrial cross-sectional area; (7) elevated levels of hepatic cytosolic malic enzyme; (8) slight decreases, significant decreases, or significant increases in serum triglyceride levels, depending on mouse strain; (9) increases in total serum cholesterol levels; (10) significant decreases in the hepatic rates of fatty acid synthesis; (11) significant increases in the hepatic rates of cholesterol synthesis; (12) decreases in both protein content and specific activity of hepatic mitochondrial carbamoyl phosphate synthetase-I without concomitant changes in serum urea nitrogen; (13) induction of glutathione S-transferase activity in liver; (14) decrease in hepatic endogenous protein phosphorylation; (15) increase in hepatic AMPase and GTPase activities; (16) formation of 5-androstene-3 beta,17 beta-diol as a major metabolite of DHEA by subcellular fractions of liver, which is reflected in serum and tissue levels; and (17) reduction in serum prolactin levels.

Women with steroid 5 alpha-reductase 2 deficiency have normal concentrations of plasma 5 alpha-dihydroprogesterone during the luteal phase.

Steroid 5 alpha-reductase 2 deficiency has been identified in two adult women from unrelated families, one a homozygote and the other a compound heterozygote. The homozygote carries the G183S mutation and is the sister of an affected male; the compound heterozygote (R246W/splice junction abnormality) is married to a heterozygote (splice junction abnormality) and is the mother of two compound heterozygotes and two homozygotes. The fact that these two women are the mothers of seven children and appear to be endocrinologically normal confirms the previous deduction that this disorder is not manifest in women.

Steroid cell tumor associated with primary amenorrhea and virilization.

A 22-year-old woman sought medical advice because of primary amenorrhea and virilization that was manifested by facial hirsutism, temporal balding, and clitorimegaly. Plasma steroid levels were determined at the time of initial assessment; androstenedione and testosterone were increased in comparison with normal values. Vaginal ultrasonography revealed the presence of a mass localized to the right ovary.

Compartmentalization of type I 17 beta-hydroxysteroid oxidoreductase in the human ovary.

The steroid-metabolizing enzyme, type I 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) also called 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) plays a key role in ovarian synthesis of 17 beta-estradiol. This is the only enzyme in the steroid-metabolizing pathway which has not been localized in the human ovary by immunohistochemistry. In this study, using antibody directed against human placental cytosolic 17 beta-HSOR (type I), a single protein band with a relative molecular mass of approximately 34 kDa was demonstrated by Western analysis in both human luteinized granulosa cells and placental tissue.

Steroid secretory characteristics of a virilizing adrenal adenoma in a woman.

A tumour of the left adrenal gland was identified in a woman who presented with virilization and secondary amenorrhea. Preoperatively, the plasma levels of dehydroepiandrosterone sulphate, dehydroepiandrosterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol were elevated two- to fourfold whereas those of urinary 17-ketosteroids were elevated more than tenfold. The production rate of dehydroepiandrosterone sulphate was more than 16 times that in normal women whereas those of dehydroepiandrosterone, testosterone and androstenedione were approximately twofold greater; plasma testosterone was derived almost entirely from the peripheral conversion of androstenedione.

Regulation of expression of the 3 beta-hydroxysteroid dehydrogenases of human placenta and fetal adrenal.

The appropriate expression of 3 beta-hydroxysteroid dehydrogenase/delta 5-->4-isomerase (3 beta-HSD) is vital for mammalian reproduction, fetal growth and life maintenance. Several isoforms of 3 beta-HSD, the products of separate genes, have been identified in various species including man. Current investigations are targeted toward defining the processes that regulate the levels of specific isoforms in various steroidogenic tissues of man.

Induction of murine hepatic glutathione S-transferase by dietary dehydroepiandrosterone.

The naturally occurring steroid dehydroepiandrosterone (DHEA), when administered as a supplement to the diet of mice and rats, produces alterations in the relative concentrations of specific liver proteins; among these, a protein of Mr approximately 28 K is markedly induced by DHEA action. In the present study we identified the murine hepatic approximately 28 kDa protein as glutathione S-transferase subtype GT-8.7.

Multiple isoforms of 3 beta-hydroxysteroid dehydrogenase/delta 5-->4-isomerase in mouse tissues: male-specific isoforms are expressed in the gonads and liver.

Multiple isoforms of 3 beta-hydroxysteroid dehydrogenase/delta 5-->4-isomerase (3 beta HSD) are expressed in various mouse tissues in a tissue-specific, sex-specific, and developmental manner. Three distinct immunoreactive species [molecular masses, 47, 44, and 42 kilodaltons (kDa)] are detectable by Western immunoblot analysis using a 3 beta HSD antiserum. Different immunoreactive isoforms are expressed in steroidogenic (44 and 47 kDa in gonads) and nonsteroidogenic (42 and 47 kDa in liver and kidney) tissues.

3 beta-hydroxysteroid dehydrogenase activity in tissues of the human fetus determined with 5 alpha-androstane-3 beta,17 beta-diol and dehydroepiandrosterone as substrates.

3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD)/delta 5-->4-isomerase activity in steroidogenic tissues is required for the synthesis of biologically active steroids. Previously, by use of dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one, DHEA) as substrate, it was established that in addition to steroidogenic tissues 3 beta-HSD/delta 5-->4-isomerase activity also is expressed in extraglandular tissues of the human fetus. In the present study, we attempted to determine whether the C-5,C-6-double bond of DHEA serves to influence 3 beta-HSD activity.

5 alpha-androstane-3,17-dione in peripheral plasma of men and women.

An antibody to androstanedione obtained in a rabbit by immunization with androstenedione-7 alpha-carboxymethyl-thioether conjugated to bovine serum albumin was found to cross-react 100% with 5 alpha-androstane-3,17-dione, a property that was used to develop a radioimmunoassay for this steroid. Plasma 5 alpha-androstane-3,17-dione concentrations were determined in young men, and in women throughout an ovulatory cycle. In the men (n = 6), plasma 5 alpha-androstane-3,17-dione concentrations were in the range of 84 to 273 pg/ml with a mean (+/- SD) value of 164 +/- 57 pg/ml.

3 beta-Hydroxysteroid dehydrogenase activity in glandular and extraglandular human fetal tissues.

The expression of 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in steroidogenic tissues is an absolute requirement for mammalian reproduction, fetal growth, and life maintenance. We sought to identify extraglandular tissue sites in the human fetus where 3 beta HSD is expressed. To this effect, we conducted in vitro studies by use of homogenates prepared from second trimester fetal tissues.

Inhibition of carbamoyl phosphate synthetase-I by dietary dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA), administered per os, serves to prevent or retard the development of a variety of genetic and induced disorders in mice and rats. This treatment also results in the development of hepatomegaly, a change of liver color from pink to mahogany, peroxisome proliferation in hepatocytes and alterations in hepatocyte mitochondria morphology and respiration. We used one- and two-dimensional polyacrylamide gel electrophoresis (PAGE) to identify changes in the relative levels of liver proteins produced by DHEA treatment of rodents.

Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5----4-isomerase expression by adrenocorticotropin in bovine adrenocortical cells.

In the steroidogenic pathway, 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta HSD) catalyzes the formation of hormonally active delta 4-3-ketosteroids from delta 5-3 beta-hydroxysteroids. In the present study the regulation of 3 beta HSD by ACTH action on bovine adrenocortical (BAC) cells in primary culture was evaluated. Western blot analysis was accomplished using an antibody against human placental 3 beta HSD.

Steroid sulfatase activity in epidermis of acne-prone and non-acne-prone skin of patients with acne vulgaris.

Abnormal keratinization of hair follicles appears to be intimately associated with acne vulgaris. Whether steroid metabolism in follicular wall keratinocytes of acne-prone skin plays a role in the development and maintenance of acne vulgaris is unknown at this time. The enzymatic hydrolysis of dehydroepiandrosterone sulfate to dehydroepiandrosterone and of estrone sulfate to estrone in cultured epidermal keratinocytes has been demonstrated.

17 beta-hydroxysteroid oxidoreductases of human fetal and adult tissues: immunological cross-reactivity with an anti-human placental cytosolic 17 beta-hydroxysteroid oxidoreductase antibody.

To determine whether the immunological determinants of human placental 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) were present in 17 beta-HSORs of tissues of the human fetus and adult and of various non-human cells maintained in culture, western immunoblot analysis was conducted by use of a polyclonal antibody directed against determinants of the placental cytosolic enzyme. Tissues and cells were evaluated for the presence of immunocross-reactive proteins with a relative molecular mass (Mr) similar to that of placental 17 beta-HSOR (approximately 34,000). By use of homogenates of human fetal tissues, immunostaining of 17 beta-HSORs of Mr approximately 34 kDa was detected in trophoblast, fetal adrenal neocortex, fetal zone of the adrenal gland, liver, intestine, kidney, brain, lung, skin, heart, spleen, pancreas, chorion laeve, and, occasionally, amnion.

Dehydroepiandrosterone feeding and protein phosphorylation, phosphatases, and lipogenic enzymes in mouse liver.

Dehydroepiandrosterone (DHEA) treatment is effective in preventing or delaying the onset of various genetic and induced disorders of mice and rats. Associated with the beneficial therapeutic effects exerted by action of this steroid is the development of hepatomegaly. To determine whether the changes associated with hepatomegaly also involve alterations in activities of tissue enzymes, we evaluated the effects of DHEA (0.

Peroxisome proliferation and induction of peroxisomal enzymes in mouse and rat liver by dehydroepiandrosterone feeding.

Dehydroepiandrosterone (DHEA) treatment is effective in the prevention of various genetic and induced disorders of mice and rats. In studies designed to define some of the basic mechanisms that underline the beneficial chemopreventive effects exerted by the action of this steroid, we found that the liver undergoes profound changes that result in: (i) hepatomegaly; (ii) color change from pink to mahogany; (iii) proliferation of peroxisomes; (iv) increased cross-sectional area and volume density of peroxisomes; (v) increased or decreased number of mitochondria per cell; (vi) decreased mitochondrial cross-sectional area; (vii) marked induction of the peroxisomal bifunctional protein enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase; (viii) increased activities of enoyl-CoA hydratase and other peroxisomal enzymes assayed in this study, viz. catalase, carnitine acetyl-CoA transferase, carnitine octanoyl-CoA transferase, and urate oxidase; and (ix) increased activity of mitochondrial carnitine palmitoyl-CoA transferase.

17 beta-Hydroxysteroid oxidoreductase activity in human maternal and umbilical cord sera.

The specific activity of 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) in human umbilical cord arterial serum has been reported to be similar to that of maternal serum and 5- to 15-times higher than that of cord venous serum. Based on these findings, it was proposed that 17 beta-HSOR in cord arterial serum arises from fetal tissue sources other than placenta. In the course of studies of the role of 17 beta-HSOR in the modulation of bioactive estrogen levels in the human fetus, we determined that: (i) the specific activity of 17 beta-HSOR in maternal serum is 2.

Cytochrome P-450s as toxicogenic catalysts: the influence of dehydroepiandrosterone.

The cytochrome P-450s catalyze the oxidative transformation of a large number of endogenous and exogenous chemicals in plants, insects, and mammals. One consequence of this type of reaction is the generation of highly reactive electrophilic metabolites that can react with intracellular macromolecules. It has been postulated that the initiation reaction for chemical carcinogenesis and/or cellular toxicity involves the metabolism of xenobiotics by P-450s.

Activity of 17 beta-hydroxysteroid oxidoreductase in tissues of the human fetus.

The interconversion of oestrone and oestradiol, androstenedione and testosterone, and dehydroepiandrosterone and 5-androstene-3 beta,17 beta-diol in mammalian tissues is catalysed by 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). To identify tissue sites of 17 beta-HSOR activity in the human fetus, microsomal fractions from 15 different fetal tissues obtained from first and second trimester pregnancies were used for evaluation of enzymatic activity by use of [17 alpha-3H] oestradiol as the substrate and NADP+ as the co-factor. With these reagents, the enzyme-catalysed reaction led to the production of both non-radiolabelled oestrone and NADP3H in equimolar amounts; the radioactivity associated with NADP3H was used to quantify 17 beta-HSOR activity.