Effect of dehydroepiandrosterone on human erythrocytes redox metabolism: inhibition of glucose-6-phosphate dehydrogenase activity in vivo and in vitro

Abstract In order to elucidate the role of G6PD inhibition by DHEA on erythrocyte redox metabolism, we measured: (1) G6PD activity in erythrocytes collected at different times after injection of synthetic ACTH in 13 normal subjects; (2) G6PD activity and GSH levels in erythrocytes incubated in the presence of different DHEA concentrations; (3) DHEA distribution and metabolic clearance in red cells, together with G6PD activity; (4) GSH regeneration after hydroperoxide oxidative stress in red cells preincubated in the presence of DHEA. In vivo DHEA increase elicits a clear-cut inhibition of red cell G6PD activity. Decreasing DHEA goes in step with the recovery of enzyme activity. In vitro G6PD inhibition by DHEA reaches its maximum within 10–15 min (20–25% inhibition at 10 −7 M DHEA concentration) and the recovery time is dosedependent. More than 2 3 of DHEA is concentrated in the red cell after 5 min incubation. GSH levels change in step with G6PD activity. After oxidative stress by BHP, DHEA-treated cells fail to restore normal GSH concentrations. These results show that DHEA inhibits human erythrocyte G6PD activity at concentrations usually observed after ACTH plasma increase and increases red cell sensitivity to oxidant agents. Moreover, it is possible that the high DHEA concentrations present in target tissues may interfere with metabolic pathways in which NADPH is the cofactor.