Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the peroxisome proliferators activated receptor alpha, pregnane X receptor, and estrogen receptor by DHEA and its metabolites have been demonstrated. Several membrane-associated receptors have also been elucidated leading to additional mechanisms by which DHEA may exert its biological effects. This review will provide an overview of the receptor multiplicity involved in the biological activity of this sterol.

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Mouse sarcoma ascites cells do not utilize fully their capacity for protein synthesis. A considerable portion of their ribosomes occur as inactive monomers. Also, a substantial amount of the cellular mRNA is in the form of ribonucleoprotein particles that sediment in the 20-70S range. This is indicated both by measurements of poly(A) content and by translation of the RNA in cell-free systems. The opulation of polypeptides synthesized under the direction of e RNA from these particles is less heterogeneous than that directed by RNA from polysomes. The mRNAs for some polypeptides are present predominantly in the small particles. Others are distributed to varying degrees between particles and polysomes. Incubation of the cells with cycloheximide drives most of the ribosomal monomers and a portion of the untranslated mRNA into polysomes. Some of the mRNAs that were predominantly in the inactive fraction seem to be refractory to this treatment.Particles released from polysomes in cells subjected to starvation are quite effective in promoting polypeptide synthesis in a reticulocyte cell-free system and cause the synthesis of a population of polypeptides similar to that coded by the polysomal RNA. The particles from cells exposed to cycloheximide are inactive but yield active RNA upon deproteinization. It is suggested that some mRNA species are maintained in an inactive state in the cell by a component of the nucleoprotein complex.

Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid precursor to the gonadal steroids. In humans, circulating levels of DHEA, as its sulfated conjugate, are high at puberty and throughout early adulthood but decline with age. Dietary supplementation to maintain high levels of DHEA purportedly has beneficial effects on cognitive memory, the immune system, and fat and carbohydrate metabolism. In rodents, DHEA is a peroxisome proliferator that induces genes for the classical peroxisomal and microsomal enzymes associated with this response. These effects are mediated through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣). However, DHEA can affect the expression of genes independently of PPAR␣, including the gene for the major inducible drug and xenobiotic metabolizing enzyme, cytochrome P450 3A23. To elucidate the biochemistry associated with DHEA treatment, we employed a cDNA gene expression array using liver RNA from rats treated with DHEA or the classic peroxisome proliferator nafenopin. Principal components analysis identified 30 to 35 genes whose expression was affected by DHEA and/or nafenopin. Some were genes previously identified as PPARresponsive genes. Changes in expression of several affected genes were verified by quantitative reverse transcriptase-polymerase chain reaction. These included aquaporin 3, which was induced by DHEA and to a lesser extent nafenopin, nuclear tyrosine phosphatase, which was induced by both agents, and 11␤-hydroxysteroid dehydrogenase 1, which was decreased by treatment with DHEA in a dose-dependent fashion. Regulation of 11␤-hydroxysteroid dehydrogenase 1 expression is important since the enzyme is believed to amplify local glucocorticoid signaling, and its repression may cause some of the metabolic effects associated with DHEA.

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