Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We ...
Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ${\sim}5$ fold and glucose 6-phosphate dehydrogenase activities were decreased by ${\sim}25%$ compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased siguificantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to fimction in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.
Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ${\sim}5$ fold and glucose 6-phosphate dehydrogenase activities were decreased by ${\sim}25%$ compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased siguificantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to fimction in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.
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대상 데이터
Six-week-old male Sprague Dawley rats were purchased from Seould National University and housed at the animal care facility at Seoul National University (Seoul, Korea). All rats were kept under standard temperature, humidity, and timed lighting conditions and were provided with rat chow and water ad libitum.
데이터처리
TOD). However, in the combination group (TED), the enzyme activity was not suppressed as seen in DHEA-only treated animals, a, b, c; one-way ANOVA, p<0.05.
One-way ANOVA test was used to determine significance (n=6~9 each). Means with different subscripts are significantly different at p<0.05 by Duncan's multiple range test.
Activities were normlaized against protein concentration. One-way ANOVA test was used to determine significance (n=6~9 each). Means with different subscripts are significantly different at p<0.
Data are expressed as mean 土 SE. SAS software was used for Duncan's multiple range test and one-way ANOVA to detennine statistical differences (p<0.05).
성능/효과
, 2001). It is possible that because we measured total levels of cytochrome P-450 in this study, we may not have found any difference in the overall levels and may have missed isozyme-specific effects of DHEA.
참고문헌 (18)
1 Allolio B Arlt W Hahner S DHEA: Why, when, and how much-DHEA replacement in adrenal insufficiency Ann Endocrinol (Paris) 2007 68 268 273 17689478
3 Champe PC Harvey RA Winters R Schott J Hexose monophosphate pathway Biochemistry 1987 USA Lippincott-Raven, Philadelphia, Pennsylvania 111 113
4 Fitzpatrick JL Ripp SL Smith NB Pierce WM Prough RA Jr Metabolism of DHEA by cytochromes P450 in rat and human liver microsomal fractions Arch Biochem Biophys 2001 389 278 287 11339818
5 Frederiks WM Van Noordan CJ Aronson DC Marx F Bosch KS Jonges GN Vogels IM James J Quantitative changes in acid phosphatase, alkaline phosphatase and 5'-nucleotidase activity in rat liver after experimentally induced cholestasis Liver 1990 10 158 166 2385157
6 Ito N Tsuda H Tatematsu M Inoue T Tagawa Y Aoki T Uwagawa S Kagawa M Ogiso T Masui T Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats-an approach for a new medium-term bioassay system Carcinogenesis 1988 9 387 394 3345580
7 Kim S Choi H Effects of vitamin E and dehydroepiandrosterone on the formation of preneoplastic lesions in rat hepatocellular carcinogenesis The Korean Journal of Nutrition 2005 38 364 372
8 Labrie F Drug insight: breast cancer prevention and tissue-targeted hormone replacement therapy Nat Clin Pract Endocrinol Metab 2007 3 584 593 17643129
9 Ladriere L Laghmich A Malaisse-Lagae F Alaisse WJ Effect of dehydroepiandrosterone in hereditarily diabetic rat Cell Biochem Funct 1997 15 287 292 9415976
10 Lohr GW Waller HD Bergmeyer HU Glucose 6-phosphate dehydrogenase Methods in enzymatic analysis, (2) 1974 New York. USA AP. 636 643
11 Marrero M Prough RA Frenkel RA Milewich L Dehydroepiandrosterone feeding and protein phosphorylation, phosphatases, and lipogenic enzymes in mouse liver Proc Soc Exp Biol Med 1990 193 110 117 2153982
12 Muller A Pallauf J Effect of increasing selenite concentrations, vitamin E supplementation and different fetal calf serum content on GPx1 activity in primary cultured rabbit hepatocytes J Trace Elem Med Biol 2003 17 183 192 14968931
13 Ochoa S Lowenstein JM Malic enzyme Methods in enzymology 1969 New York, USA AP. 230 237
14 Omura T Sato R The Carbon Monoxide-Binding Pigment of Liver Microsomes. I. Evidence for Its Hemoprotein Nature J Biol Chem 1964 239 2370 2378 14209971
15 Roberge C Carpentier C Langlois M Baillargeon J Ardilouze J Maheux P Gallo-Payet N Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab 2007 293 E1465 E1478 17911338
16 Tappel AL Glutathione peroxidase and hydroperoxides Methods Enzymol 1978 52 506 513 672654
17 Wu HQ Masset-Brown J Tweedie DJ Milewich L Frenkel RA Martin-Wixtrom C Estabrook RW Prough RA Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator Cancer Res 1989 49 2337 2343 2523237
18 Zhao S Ma H Zou S Chen W Effects of in ovo administration of DHEA on lipid metabolism and hepatic lipogenetic genes expression in broiler chickens during embryonic development Lipids 2007 42 749 757 17574488
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