YOU ARE NOW CONNECTED TO THE TOXLINE (1981 FORWARD, NON-ROYALTY) FILE. ==DHEA - DEHYDROEPIANDROSTERONE== 4 AUTHOR Schwartz AG AUTHOR Pashko LL TITLE Cancer chemoprevention with the adrenocortical steroid dehydroepiandrosterone and structural analogs. SOURCE J Cell Biochem Suppl; VOL 17G, 1993, P73-9 (REF: 43) ABSTRACT Dehydroepiandrosterone (DHEA) is an adrenocortical steroid that produces broad-spectrum cancer chemopreventive action in mice and rats. In the mouse two-stage skin tumorigenesis model, DHEA treatment inhibits tumor initiation, as well as tumor promoter-induced epidermal hyperplasia and promotion of papillomas. There is considerable evidence that DHEA exerts its anti-proliferative and tumor-preventive action through the inhibition of glucose-6-phosphate dehydrogenase and the pentose phosphate pathway, which generate NADPH (required for mixed-function oxidase activation of chemical carcinogens, as well as for deoxyribonucleotide synthesis) and ribose 5-phosphate (also required for deoxyribonucleotide synthesis). Long-term DHEA treatment of mice also reduces weight gain (apparently by enhancing thermogenesis), and appears to produce many of the beneficial effects of food restriction, which have been shown to inhibit the development of many age-associated diseases, including cancer. Using the mouse two-stage skin tumorigenesis model, we found that adrenalectomy completely reverses the anti-hyperplastic and antitumor-promoting effects of food restriction. It is not unlikely that food restriction stimulates enhanced levels of adrenocortical steroids, such as the anti-inflammatory glucocorticoids and DHEA, which in turn mediate the tumor-inhibitory effect of underfeeding. 9 AUTHOR Estabrook RW AUTHOR Milewich L AUTHOR Prough RA TITLE Cytochrome P-450s as toxicogenic catalysts: the influence of dehydroepiandrosterone. SOURCE Princess Takamatsu Symp; VOL 21, 1990, P33-44 (REF: 30) ABSTRACT 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. The naturally occurring steroid dehydroepiandrosterone (DHEA), when administered as a supplement to the diet of rodents, has been reported to have anti-carcinogenic and other chemoprotective activities. A change in the inventory of liver P-450s occurs during treatment of rodents with DHEA, the most pronounced being that involved in the omega-hydroxylation of medium-chain length fatty acids. In addition, changes in the activities of other liver P-450s, viz., P-450IIB1, P-450IIC11, and P-450IIIA, occur as shown by in vitro experiments to assess the P-450-dependent formation of hydroxylated metabolites of testosterone and androstenedione. The effect of feeding rodents a diet supplemented with DHEA mimics some of the changes seen when animals are treated with hypolipidemic drugs (such as ciprofibrate, and other chemicals which are known to be peroxisome proliferators). Studies comparing the enzymatic functions of the heterologous expressed recombinant forms of P-45017 alpha, responsible for the two step conversions of progesterone and pregnenolone to the C19-steroids, androstenedione, and DHEA, respectively, illustrated the marked differences in enzymatic properties between the human and the rat orthologues. The findings serve to demonstrate that DHEA is an obligatory intermediate for the synthesis of androgens in the human, but not in the rodent. The biochemical changes responsible for the anti-carcinogenic properties of DHEA remain to be identified. The studies presented here suggest that DHEA, when administered as a dietary supplement, functions like a xenobiotic, and that its effects may result from alterations in the inventory of cellular P-450s, thereby influencing the balance of metabolic activities associated with the initiation phase of chemical carcinogenesis and/or toxicity. 11 AUTHOR Schwartz AG AUTHOR Pashko L AUTHOR Whitcomb JM TITLE Inhibition of tumor development by dehydroepiandrosterone and related steroids. SOURCE Toxicol Pathol; VOL 14, ISS 3, 1986, P357-62 (REF: 44) ABSTRACT The naturally occurring adrenal steroid, dehydroepiandrosterone (DHEA), is a potent non-competitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH). Oral administration of DHEA to mice inhibits spontaneous breast cancer and chemically induced tumors of the lung and colon. Topical application of DHEA to mouse skin inhibits 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and DMBA-induced carcinomas at both the initiation and promotion phase. Evidence is presented that critical steps in the initiation process (mixed-function oxidase activation of a carcinogen) and promotion process (enhanced rates of cell proliferation and superoxide formation) all require NADPH and may be inhibited by DHEA and structural analogs as a result of a lowering of the NADPH cellular pool. Results obtained by others with fibroblasts and lymphocytes from individuals with the Mediterranean variant of G6PDH deficiency also indicate that a reduction in the NADPH cellular pool confers resistance to benzo(a)pyrene. Preliminary data suggest that food restriction may depress G6PDH levels and this may contribute to the tumor preventive effect of underfeeding. 1 AUTHOR Laychock SG AUTHOR Bauer AL TITLE Epiandrosterone and dehydroepiandrosterone affect glucose oxidation and interleukin-1 beta effects in pancreatic islets. SOURCE Endocrinology; VOL 137, ISS 8, 1996, P3375-85 ABSTRACT Isolated rat islets or RINm5F insulinoma cells treated with interleukin-1 beta (IL-1 beta) for 18 h show reduced glucose-sensitive insulin release and increased nitrite formation as a result of nitric oxide synthase induction. Although a phosphodiesterase inhibitor, isobutylmethylxanthine, potentiated insulin release in response to glucose stimulation, the secretory response was not restored to normal in IL-1 beta-treated islets. Islets that were cultured for 18 h in the presence of IL-1 beta and epiandrosterone (EA) or dehydroepiandrosterone (DHEA) and then washed responded with a concentration-dependent reversal of the effects of IL-1 beta on insulin release in the presence of a glucose or glucose plus isobutylmethylxanthine stimulus. In contrast, when EA and DHEA were not washed from the islets before determination of insulin release, the presence of EA or DHEA inhibited insulin release in both freshly isolated and cultured islets. Nitrite formation in islets and RINm5F cells in response to IL-1 beta was also significantly reduced during culture with EA or DHEA, although nitrite levels were still elevated above control values. Neither steroid affected cell growth or DNA or protein content. Pyrrolidine dithiocarbamate also reduced IL-1 beta-induced nitrite formation. EA and DHEA inhibited [U-14C]glucose oxidation in islets and RINm5F cells. Comparison of [1-14C]glucose and [6-14C]glucose oxidation in islets and RINm5F cells when EA was present during culture and metabolic determination indicated that EA inhibited glycolysis and the pentose shunt contribution to glucose utilization. Neither IL-1 beta in islets nor DHEA in RINm5F cells inhibited pentose shunt activity, although total glucose oxidation and utilization were inhibited. The effects of DHEA and EA on glucose oxidation were rapidly reversible. EA and DHEA reduced glucose-6-phosphate dehydrogenase activity only when added directly to tissue homogenates. Thus, EA and DHEA antagonize the effects of IL-1 beta on beta-cells. Inhibition of glucose metabolism and pentose shunt activity may protect the cells from nitric oxide synthase activation and related toxicities. 11 AUTHOR Gordon GB AUTHOR Shantz LM AUTHOR Talalay P TITLE Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone. SOURCE Adv Enzyme Regul; VOL 26, 1987, P355-82 (REF: 94) ABSTRACT Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHEA) and its conjugates are abundant circulating steroids that originate largely from the adrenal cortex. Their levels decline profoundly with age in human beings of both sexes, as the incidence of most cancers rises. Low levels of these steroids have been associated with the presence and risk of development of cancer. Administration of DHEA to rodents produces protection against spontaneous tumors and chemical carcinogenesis, suppresses weight gain without significantly affecting food intake, ameliorates the severity of diabetes in genetically diabetic mice, and restrains autoimmune processes. DHEA and related steroids also depress the mitogenic effects of carcinogens, tumor promoters and plant lectins, and block viral and carcinogen-induced cell transformations. DHEA and certain congeners are also potent and quite specific inhibitors of mammalian glucose-6-phosphate dehydrogenases. We have observed that the conversion of 3T3-L1 and 3T3-F442A preadipocyte clones to the adipocyte phenotype, in response to appropriate differentiation stimuli (fetal calf serum, insulin, dexamethasone, and 1-methyl-3-isobutylxanthine), is blocked by DHEA and other steroidal inhibitors of glucose-6-phosphate dehydrogenase. The structural requirements for blocking adipocyte differentiation and for inhibiting glucose-6-phosphate dehydrogenase are closely correlated. Evidence is reviewed suggesting that the inhibition of glucose-6-phosphate dehydrogenase is central to the anticarcinogenic and differentiation-blocking actions of DHEA and related steroids. The 3T3 preadipocyte clones provide a valuable system for the analysis of the mechanisms of the effects of DHEA on growth, differentiation and carcinogenesis. YOU ARE NOW CONNECTED TO THE MEDLINE (1994 - 97) FILE. 3 AUTHOR Nakashima N AUTHOR Haji M AUTHOR Umeda F AUTHOR Nawata H TITLE Effect of dehydroepiandrosterone on glucose uptake in cultured rat myoblasts. SOURCE Horm Metab Res 1995 Nov;27(11):491-4 ABSTRACT The effects of dehydroepiandrosterone (DHEA) on glucose uptake and on insulin sensitivity were studied in cultured rat myoblasts (L6 cells). Preincubation with supraphysiological doses of DHEA (10(-5) M approximately significantly enhanced (p < 0.05) the cellular uptake of [3H]-2-deoxyglucose. Glucose uptake was significantly increased in cells exposed to 10(-4)M DHEA for 10 hours (p < 0.005), and for 24 hours (p < 0.001), but not for 3 hours. An increase in DHEA sensitivity with an enhanced glucose uptake was observed in cells exposed to 10(-7)M of human insulin. Insulin sensitivity was increased by preincubating the cells with 10(-6)M of DHEA. Other androgens enhanced the effect on glucose uptake to a lesser extent. DHEA sulfate had no effect on L6 cells, suggesting that the effect may be specific for DHEA, not common to androgens, Sulfation of DHEA may negate the effect. In reciprocal plot analysis, the Km value for glucose transport was decreased by preincubation with DHEA (from 0.67 mM without DHEA, 0.56mM with 10(-5)M DHEA, and 0.25mM with 10(-4) M DHEA), although Vmax was unchanged, We conclude that DHEA increases the affinity of glucose transport in the plasma membrane of cultured rat myoblasts, leading to an enhanced glucose uptake and an increase in insulin sensitivity.