No abstract

Free radical overproduction contributes to tissue damage induced by acute hyperglycemia. Dehydroepiandrosterone, which has recently been found to have antioxidant properties, was administered i.p. to rats at different doses (10, 50 or 100 mg/kg body weight) 3 h before treatment with dextrose (5 g/kg). Lipid peroxidation was evaluated on liver, brain and kidney homogenates, measuring both steady-state concentrations of thiobarbituric acid reactive substances, and fluorescent chromolipids, evaluated as hydroxynonenal adducts. Formation of thiobarbituric acid reactive substances was significantly higher in hyperglycemic than in normoglycemic animals. Three hours (but not 1 h) dehydroepiandrosterone-pretreatment protected tissues against lipid peroxidation induced by dextrose; both thiobarbituric acid reactive substances and hydroxynonenal adducts in liver, kidney and brain homogenates were significantly lower in dehydroepiandrosterone-pretreated animals. Dehydroepiandrosterone did not modify the cytosolic level of antioxidants, such as alpha-tocopherol or glutathione, nor the activities of glutathione peroxidase, reductase or transferase. The results of this study indicate that the 'in vivo' administration of dehydroepiandrosterone increases tissue resistance to lipid peroxidation triggered by acute hyperglycemia.

Pericyte loss is an early feature of diabetic retinopathy and represents a key step in the progression of this disease. This study aimed to evaluate the effect of dehydroepiandrosterone (DHEA) on glucose toxicity in retinal capillary pericytes. Bovine retinal pericytes (BRP) were cultured in a high glucose concentration, with or without DHEA. After 4 days of incubation the number of BRP was significantly reduced by the high glucose concentration. The addition of DHEA to the medium reversed the adverse effect of high glucose: BRP proliferation partially recovered in the presence of 10 nmol/l DHEA, and completely recovered in the presence of DHEA at concentrations equal to or greater than 100 nmol/l. At physiological glucose concentrations, DHEA had no effect on BRP growth. Data show that DHEA, at concentrations similar to those found in human plasma, protects BRP against glucose toxicity. This effect seems specific for DHEA, since its metabolites, 5-en-androstene-3 ,17 -diol, dihydrotestosterone and estradiol did not alter BRP growth in normal or high glucose media. Various pieces of evidence link the antioxidant properties of DHEA to its protective effect on glucose-induced toxicity in BRP.

Summary Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA) exerts a protective effect against breast cancer. It has been proposed that the non-competitive inhibition of glucose-6-phosphate dehydrogenase (G6PD) contributes to DHEA antitumour action. We evaluated the effects of DHEA on G6PD activity and on the in vitro proliferation of two human breast cancer cell lines, MCF-7 (steroid receptor positive) and MDA-MB-231 (steroid receptor negative), in a serum-free assay. DHEA inhibition of G6PD was only found to occur at concentrations above 10 gm; at these high concentrations, the growth curve was parallel to the enzyme inhibition curve in both cell lines. In contrast, at concentrations in the in vivo breast tissue concentration range, neither cell growth nor enzyme activity was inhibited. The results failed to confirm DHEA's putative anti-tumour action on breast cancer through G6PD inhibition, as the enzyme blockade only becomes apparent at pharmacological concentrations of the steroid.

Objective: Dehydroepiandrosterone (DHEA) is a widely studied steroid hormone with multi-functional properties. Reports suggest that some of the many activities of DHEA are due to its protective effect against lipid peroxidation. Nevertheless, the antioxidant properties of DHEA are still the subject of debate. The aim was to evaluate whether its two opposed effects on lipid peroxidation reported in the literature may be dependent on schedule and doses used. Methods: Chang liver cells, a line derived from normal human liver, were grown in media containing either no steroids (control) or DHEA at concentrations ranging from 0.1 mmol/l to 50 mmol/l. At specific times, cultures were halted and cells received a pro-oxidant stimulus (cumene (CuOOH) 0.5 mmol/l), at which time cell viability (by trypan blue staining and lactate dehydrogenase (LDH) release) and thiobarbituric acid reactive substances (TBARS) concentration (spectrophotometrical assay) were evaluated. Results: At concentrations ranging from 0.1 mmol/l to 1 mmol/l, DHEA protects Chang liver cells against lipid peroxidation and/or death induced by cumene. This effect disappears if the concentration is increased to 10 mmol/l; at higher concentrations (50 mmol/l) a pro-oxidant/cytotoxic effect of DHEA appears. Conclusions: DHEA exhibits two opposed effects on lipid peroxidation; depending on its concentration it acts either to limit or to induce oxidative stress. The threshold concentration at which the pro-oxidant activity of DHEA prevails is not far in excess of that having an antioxidant effect. Either effect of DHEA on lipid peroxidation is only evident after a 'lag-phase'.