Differential effects of dehydroepiandrosterone and deoxyribonucleosides on DNA synthesis and de novo cholesterogenesis in hepatocarcinogenesis in rats.
ABSTRACT Previous studies from our laboratory have shown that dehydroepiandrosterone (DHEA), an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), prevents the development of gamma-glutamyltranspeptidase (GGT)-positive foci in the early stages of hepatocarcinogenesis in rats. Since high rates of DNA and cholesterol (CH) synthesis are observed during promotion of carcinogenesis, and mevalonate (MVA), or some other intermediates of CH synthesis, could be mediators of DNA synthesis, we investigated the effect of DHEA on CH synthesis in rat liver during the development of GGT-positive foci. Hepatocarcinogenesis was induced by diethylnitrosamine in female Wistar rats by the Solt-Farber protocol (initiation/selection) with and without phenobarbital treatment. A 15 day treatment with DHEA (0.6% in the diet), started after selection, caused a great fall in labeling and mitotic indices of GGT-positive foci, which was prevented by the simultaneous administration of a mixture of four deoxyribonucleosides (DRNs) of adenine, guanine, cytosine and thymine or four ribonucleosides (RNs) of adenine, guanine, cytosine and uridine, but not by the corresponding bases. DHEA greatly inhibited G6PD activity and the production of ribulose-5-phosphate, without affecting NADPH levels, due to the compensatory increase in malic enzyme and isocitric dehydrogenase activities. Serum lecithin/cholesterol acyltransferase activity underwent a reduction in conditions allowing a rapid growth of GGT-positive tissue (absence of DHEA or presence of DHEA plus DRNs or RNs). Liver slices isolated from DHEA-treated rats showed a rise in CH content, coupled with a 80% fall in the incorporation of labeled acetate, but not of labeled MVA, into CH. A 25 day treatment of rats subjected to initiation/selection, started after the appearance of persistent nodules, caused a 36 and 78% fall in the incorporation, in vivo, of 3H2O into nodular and surrounding liver CH respectively. DRN did not counteract DHEA-induced inhibition on CH synthesis. Thus DHEA inhibits the CH biosynthetic pathway before MVA synthesis, in conditions (presence of DHEA plus DRN/RN) allowing rapid growth of preneoplastic lesions. Therefore, the development of these lesions does not need the synthesis of large amounts of CH and CH metabolites. Thus, the antipromotion effect of DHEA may depend on a decreased availability of pentose phosphates for DNA synthesis.