Sex Differences in the Control of Glucose-6-phosphate Dehydrogenase and 6-Phosphogluconate Dehydrogenase. Interaction of Estrogen, Testosterone and Insulin in the Regulation of Enzyme Levels in vivo and in Cultured Hepatocytes

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Abstract
Control of the activities of glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malate dehydrogenase was investigated in intact rats and in hepatocyte cultures. 1) Adult females had 2-fold greater activities of hepatic glucose-6-phosphate- and 6-phosphogluconate dehydrogenases than adult males, but similar activities of malate dehydrogenase. Castrated males showed decreased activities of all three enzymes in comparison to age- and weight-matched intact controls. In starved animals the activities of all three enzymes decreased significantly. After refeeding with non purified diet the activities returned to the prestarved level in females, but increased to clearly higher values in intact and castrated males. 2) Estrogen levels were in the same range in immature and adult male and female rats. Testosterone levels were highest in adult males, clearly lower in adult females (1/8) and immature males (1/8), still lower in immature females (1/15) and lowest in castrated males (1/40). A simple correlation of the sex differences in these hormone levels to sex differences in glucose-6-phosphate- and 6-phosphogluconate dehydrogenase activities was not apparent. 3) In serum-free, dexamethasone-supplemented 48-h cultures of hepatocytes from both male and female rats the basal activities of glucose-6-phosphate dehydrogenase were the same: they were increased 2-3 fold by insulin alone, 1.5 fold be estrogen alone and 4-5 fold by insulin plus estrogen. Apparently sex differences did not persist in 48-h cell cultures. 4) In 48-h cultures of male hepatocytes, then used as the experimental model, insulin alone increased the activity not only of glucose-6-phosphate dehydrogenase but also of 6-phosphogluconate and malate dehydrogenase but also of 6-phosphogluconate and malate dehydrogenase. Estrogen alone, however, enhanced only the activity of glucose-6-phosphate dehydrogenase, but not of 6-phosphogluconate- and malate dehydrogenases. Testosterone alone was without effect on the activities of the three enzymes. When added together insulin and estrogen increased glucose-6-phosphate dehydrogenase, but no 6-phosphogluconate- and malate dehydrogenases additively. Testosterone prevented the estrogen, but not the insulin response. The major conclusion from the present findings is that insulin as well as estrogen can act as direct inducers of NADPH-generating glucose-6-phosphate dehydrogenase in hepatocytes and that testosterone functions as an estrogen-but not as an insulin-antagonist in the induction of the enzyme.