Reversal by ribo- and deoxyribonucleosides of dehydroepiandrosterone-induced inhibition of enzyme altered foci in the liver of rats subjected to the initiation-selection process of experimental carcinogenesis

Abstract

The effect of dehydroepiandrosterone (DHEA) on the activity of NADPH-producing enzymes and the development of enzyme-altered foci has been investigated in the liver of female Wistar rats subjected to an initiating treatment (a necrogenic dose of diethylnitrosamine) followed, 15 days later, by a selection treatment [a 15-day feeding of a diet containing 0.03% 2-acetylaminofluorene (2-AAF), with a partial hepatectomy at the midpoint of this feeding]. At the end of the selection treatment all rat groups received, for 15 days, a basal diet containing, when indicated, 0.05% phenobarbital (PB) and/or 0.6% DHEA. The effect of DHEA on the activity of NADPH-producing enzymes was also studied in normal rats fed, for 15 days, a diet containing 0.6% DHEA and in their pair-fed controls. DHEA caused a 43-58% inhibition of glucose-6-phosphate dehydrogenase (G6PD) and, respectively, 338-420% and 21-24% increases in malic enzyme (ME) and isocitric dehydrogenase activities in all rat groups. This was coupled with a great fall in the production of ribulose-5-phosphate, while no change in NADP+/NADPH ratio occurred. Hepatocytes, isolated from DHEA-treated rats, exhibited a very low activity of hexose monophosphate shunt (HMS), which was not stimulated by methylene blue, an exogenous oxidizing agent that markedly stimulated HMS activity in control hepatocytes. DHEA caused a great fall in the percentage of liver occupied by gamma-glutamyltranspeptidase (GGT)-positive foci, in the rats subjected to the initiation-selection treatments. PB enhanced the development of these foci, an effect which was completely overcome by DHEA. In addition, focal cells no longer expressed a G6PD activity higher than that of surrounding liver in DHEA-treated rats, but exhibited a high histochemical reaction for ME. DHEA also caused a great fall in labelling index of GGT-positive foci. Starting at the end of 2-AAF feeding, a mixture of ribonucleosides (RNs) of adenine, cytosine, guanine and uracil and of deoxyribonucleosides (DRNs) of adenine, cytosine, guanine and thymine were injected i.p. every 8 h for 12 days to the rats subjected to the initiation-selection treatments plus PB. Rats were killed 3 days after the end of RN and DRN treatments. These treatments completely overcome the DHEA effect on the development of GGT-positive foci and DNA synthesis by the focal cells, without affecting G6PD activity of both whole liver and putative preneoplastic foci. Experiments with labeled nucleosides revealed that RNs and DRNs produced derivatives that were incorporated into liver DNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential expression of key enzymes of energy metabolism in preneoplastic and neoplastic rat liver lesions induced by N-nitrosomorpholine and dehydroepiandrosterone

“…G6PDH was not only more active in the liver of untreated females compared to males but was also induced more strongly in females by DHEA treatment. This agrees with our previous findings (Mayer et al, 1996) but is at variance with the data of Garcea et al (1988), who observed a decrease in G6PDH activity in liver homogenates from female rats treated for 2 weeks with 0.6% DHEA in the diet. The strong increase in ME activity is in accordance with observations of different investigators (Garcea et al, 1988;Cleary, 1990).…”

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

“…By using DHEA in combination with an initiation/selection model of hepatocarcinogenesis (Solt-Farber-protocol) that results in a large number of rapidly proliferating nodules, Garcea et al (9) observed a reduction of G6PDH activity in total liver postmitochondrial supernatant and a reduction in the number of GGT-positive liver lesions by DHEAtreatment. The same authors (6,8) reported an inhibition of [ 3 H]-thymidine incorporation and a reduction of mitotic index in rapidly proliferating hepatic nodules induced in female Wistar rats. The inhibition of thymidine incorporation could be reversed by the injection of ribo-and deoxyribonucleosides (8).…”

“…The same authors (6,8) reported an inhibition of [ 3 H]-thymidine incorporation and a reduction of mitotic index in rapidly proliferating hepatic nodules induced in female Wistar rats. The inhibition of thymidine incorporation could be reversed by the injection of ribo-and deoxyribonucleosides (8). The authors conclude that DHEA inhibits formation of preneoplastic lesions by the reduction of G6PDH activity resulting in a depletion of the tissue in ribo-and deoxyribonucleotides.…”

Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone

“…The chemoprotective and anti-proliferative actions of DHEA have been explained by several mechanisms, including the inhibition of glucose-6-phosphate dehydrogenase, 9,31,32 the suppression of farnesyl diphosphate and the cholesterol biosynthetic pathway via the inhibition of HMG-CoA reductase, 7,10,33 direct interference with the mitogen-activated protein kinase (MAPK) pathway, 34,35 and the suppression of nitric oxide generation, through downregulation of nitric oxide synthase II (iNOS). 36,37 However, it is possible that other mechanisms that have yet to be discovered also play a role in the anti-carcinogenic effects of DHEA.…”

“…[4][5][6] Induction of cell-cycle arrest by DHEA treatment has also been demonstrated in the human colonic adenocarcinoma cell line, HT-29 7 and in Ehrlich's tumor cells. 8 These effects of DHEA have not been explained completely, and several mechanisms, including the depletion of nicotinamide adenine dinucleotide phosphate, reduced (NADPH) and ribose-5-phosphate, due to the inhibition of glucose-6-phosphate dehydrogenase (G6PD) activity, 9 and suppression of the cholesterol biosynthetic pathway by the inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG)-CoA reductase (HMGR) activity, 10 would appear to contribute to these actions. However, a previous study by ourselves demonstrated that many DHEA-related steroids inhibited the activities of both these enzymes, but that the inhibition of cell growth did not correlate with inhibition of either enzyme activity.…”