• 한국식품위생안전성학회지
• /
• 제8권1호
• /
• pp.37-53
• /
• 1993

옥수수에 자연 발생하는 F. monliforme MRC 826을 옥수수에 배양하여 배양물에 존재하는 fumonisin $B_{1}$을 정성검사 한 후, 배양물질의 독성 및 발암성을 aflatoxin $B_{1}$과 비교하여 보았다. 독성 시험은 3주령의 Sprague-Dawley(SD) 암컷 랫드 10마리를 각 군당 5마리씩 2개 군으로 나누어 제1군은 시험 군으로 배양물질을 분말사료와 1 : 1로 혼합하여 1주간 급여하였고, 제 2군은 대조군으로 분말사료만을 급여하면서 실험하였다. 시험군은 급여 3~4일경부터 침울해 보였으며, 랫드 1마리당 1주간 평균 사료 섭취량은 24 g이었고, 평균 체중은 18 g 감소하였다. 부검 시 신장의 피막박리가 곤란하였고 조직 검사 결과 간장의 공포변성에 신장 세뇨관 상피세포의 괴사등의 관찰되었다. 발암성 검사 6주령의 SD 수컷 랫드 70마리를 사용하여 중기 발암성 검색법인 diethylnitrosamine-partial hepatectomy (DEN-PH) 모델로 시험하였다. 시험군은 각 군당 14마리씩 총 5개군을 두었으며 실험 0일 때 DEN을 복상내로 투여하였고, 2주후에 제 1군(양성대조군)은 aflatoxin $B_{1}$을 2ppm 농도로 첨가한 사료를, 제4군 옥수수를 5% 농도로 첨가한 사료를, 제 5군은 옥수를 2.5% 농도로 첨가한 사료를 각각 6주간 급여하였다. 실험 3주간에 간 부분 절제술을 시술하였고, 8주간 체중변화, 사료섭취량 음수량을 측정한 후 부검하여 간장은 glutathione S-transferase placental form (GST-P) 면역조직화학적 염색을 실시하였고, 뇌, 뇌하수체, 융선, 폐, 부신, 신장, 심장, 비장, 정낭선, 고환 및 간장 등은 H&E 염색을 하여 병변을 관찰하였다. GST-P 염색결과 5% 배양물질 투여군은 aflatoxin $B_{1}$투여군과 유사하게 GST-P 양성병소의 발현율이 대조군에 비하여 유의성 있는 증가를 보였다. 5% 배양물질 투여군 및 2.5% 배양물질 투여군은 옥수수 투여군에 비하여 증체율의 저하가 관찰되었고, 5% 배양물질 투여군에서 간, 신장, 고환 및 정낭선등의 체중에 대한 상대중량비, 혈액요소질소와 평균 적혈구 혈색소량 등은 옥수수 투여군에 비하여 유의성 있는 변화가 관찰되었다. 이상의 결과들을 종합해 볼 때 F. monliforme MRC 826 배양물질은 랫드의 간과 신장에 독성을 나타내었고, aflatoxin $B_{1}$과 마찬가지로 간암 촉진효과가 있는 것으로 판단되었다.

• 한국수의병리학회지
• /
• 제1권1호
• /
• pp.33-39
• /
• 1997

We investigated metabolism and carcinogenesis in livers of Sprague-Dawley rats fed juices and pelleted diets containing Korean native plants petasites japonicus Maxim by evaluating cell localization and expression of cytochrome P450s and GST-P. Anti-cytochrome P450s application in liver sections revealed three to four times increased expression of cytochrome P450E1 immunoreactivity in degenerative hepatocytes when compared to histologically normal hepatocytes. Anti-GST-P in showed positive pren plastic foci as well as in individual hepatocytes randomly scattered throughout all liver sections examined. Additionally GST-P was evident in proliferative endothelial cells and biliary epithelial cells in exposed rat livers. These results suggested that the increased level of cytochrome P4502E1 in affected hepatocytes was a direct consequence of Petasites japonicus toxicity. Further immunoreactivity to anti-GST-P in hepatocytes endothelial cells and biliary epithelial cells indicated a possible preneoplastic effects of Petasites japonicus in Sprague-Dawley rat.

• Nutrition Research and Practice
• /
• 제2권2호
• /
• pp.80-84
• /
• 2008

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.

• 고려인삼학회:학술대회논문집
• /
• 고려인삼학회 2002년도 학술대회지
• /
• pp.277-287
• /
• 2002

The chemopreventive effects of ginseng on rat carcinogenesis models were investigated, In the present study, the inhibitory effects of white and red ginseng on tumor development were examined using medium-term liver, initiation and medium-term multi-organ carcinogenicity bioassay systems. No modifying potential of the ginsengs was evident in terms of the numbers or areas of glutathione S-transferase placental form (GST -P)-positive foci, which is a marker of preneoplastic lesion in rat livers. However, white ginseng, but not red ginseng was found to decrease the incidences of adenocarcinoma of the small intestine and colon in the medium-term multi-organ carcinogenesis model. These results indicate that white ginseng may have inhibitory effects on progression stage of rat intestinal carcinogenesis, but the influence is not strong. Ginseng is unlikely to have promoting or inhibitory effects in other organs under the present type of experimental conditions. Possible application on ginseng for chemoprevention of colon cancer in humans, can be concluded given the lack of obvious adverse effects.

• Journal of Nutrition and Health
• /
• 제33권1호
• /
• pp.23-32
• /
• 2000

The purpose of this study was to investigate the effcts of n-3, n-6 fatty arid and d-limonene on histopathological and biochemical changes in experimental rat hepatocarcinogenesis. To attain the above objectives, weanling Sprague-Dawley female rats were intraperitoneally injected twice with a dose of diethylnitrosamine(DEN, 50mg/kg body weight) and after 1 week 0.05% phenobarbital was provided with water. Sardine oil rich in n-3 fatty acids and corn oil rich in n-6 fatty acids were fed at 15% by weight and 5% d-limonene was added to the diet in each group. Ten weeks or 20 weeks after DEN treatment, rats were sacrifirced. The formation of glutathione S-transferase placental form positive(GST-P$\^$+/) foci was significantly decreased by the treatment of either sardine oil or d-limonene HMG-CoA reductase activity was not affected by dietary oils and d-limonene. Protein kinase C (PKC) activity was decreased by either sardine oil or d-limonene. Particularly d-limonene decreased the membrane PKC activity. Membrane Cholesterol/Phospholipid(Chol/PL) ratio was significantly decreased by d-limonene in sardine oil group. The data showed that GST-P$\^$+/ foci number was positively correlated with membrane PKC activity and serum cholesterol and negatively correlated with liver cholesterol level. These results suggest informations about the correlation between histopathological and biochemical changes such as cholesterol metabolism and PKC activity in experimental hepatocarcinogenesis and thereby can elucidate the possible mechanism related to the cancer inhibition.(Korean J Nutrition 33(1) : 23-32, 2000)

• Toxicological Research
• /
• 제34권4호
• /
• pp.291-296
• /
• 2018

Chemical carcinogenesis is a multistep process. Genotoxic carcinogens, which are DNA-reactive, induce DNA adduct formation and genetic alterations in target cells, thereby generating mutated cells (initiation). Subsequently, preneoplastic lesions appear through clonal proliferation of the mutated cells and transform into tumors (promotion and progression). Many factors may influence these processes in a dose-dependent manner. Therefore, quantitative analysis plays an important role in studies on the carcinogenic threshold of genotoxic carcinogens. Herein, we present data on the relationship between key carcinogenic events and their deriving point of departure (PoD). Their PoDs were also compared to those of the carcinogenesis pathway. In an experiment, the liver of rats exposed to 2-amino-3,8-dimethylimidazo-(4,5-f)quinoxaline (MeIQx) was examined to determine the formation of MeIQx-DNA adducts, generation of mutations at LacI transgene, and induction of preneoplastic glutathione S-transferase placental form (GST-P)-positive foci and tumors (benign and malignant). The PoDs of the above key events in the carcinogenicity of MeIQx were increased as the carcinogenesis advanced; however, these PoDs were lower than those of tumor induction. Thus, the order of key events during tumor induction in the liver was as follows: formation of DNA adducts ${\ll}$ Mutations ${\ll}$ GST-positive foci (preneoplasia) ${\ll}$ Tumor (adenoma and carcinoma). We also obtained similar data on the genotoxic and carcinogenic PoDs of other hepatocarcinogens, such as 2-amino-3,8-dimethylimidazo(4,5-f)quinoline. These results contribute to elucidating the existence of a genotoxic and carcinogenic threshold.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
• /
• pp.339-339
• /
• 1994

It has been reported that Indole-3-carbinol (I3C), a naturally occurring compound In cruclferous vegetables, exerts anticarcinogenic activity In several organs In rodents. The modifying effects of I3C were therefore assessed uging a rat multi-organ carcinogenesis model. A total of 100 male Sprague-Dawley rats were divided Into 3 groups. Animals of groups 1 and 2 were sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., i.p.), N-methylnitrosourea (NNU; 20 mg/kg b.w., 4 times for 2 weeks, i.p), and dihydroxy-di-N-propylnitrosauine (DHPN; 0.1% In d.w. for 2 weeks) for 4 weeks (DMD treatment). Animals of groups 1 and 3 were given the diet of 0.25% I3C for 20 weeks after DMD initiation and then were given basal diet for 28 weeks. All animals were sacrificed at week 24 and 52, respectively. I3C has been clearly demonstrated promoting effects on the development of glutathione S-transferase placental form (GST-P) positive hepatic foci at 24 weeks of the experiment. And I3C also exerted promoting potential In the hepatocellular adenoma (4/14; 29%) and the adenoma (7/14; 50%) of the thyroid gland at 52 weeks of the experiment. Therefore, I3C may promote hepatocarcinogenesis and thyroid tumorigenesis in the rat multi-organ carcinogenesis model.

• Journal of Nutrition and Health
• /
• 제35권6호
• /
• pp.643-649
• /
• 2002

This study was done to investigate effects of ${\gamma}$-irradiated pork feeding on the formation of glutathione S-transferase placental form positive (GST-P$^{+}$) foci, lipid peroxidation, cytochrome P450 system and microsomal glucose 6-phosphatase activity in diethylnitrosamine (DEN)-initiated rat hepatocarcinogenesis. Weaning Sprague-Dawley male rats were fed the diet containing ${\gamma}$-irradiated ground pork at the dose of 0, 3, 10, 30 kGy as a 20％ of protein source for 8 weeks. One week after feeding, rats were intraperitoneally injected twice with a dose of DEN (50 mg/kg BW). As a promote.,0.05％phenobarbital was fed in drinking water from one week after DEN treatment until the end of experiment. At the end of 8th week, rats were sacrificed and hepatic GST-P$^{+}$ foci, microsomal malondialdehyde (MDA) and conjugated diene contents were determined. In addition, cytochrome P450 content and the activities of NADPH cytochrome P450 reductase and glucose 6-phosphatase were also measured. There was no significant effect by gamma irradiation on microsomal MDA content, conjugated diene, cytochrome P450 content and activities of NADPH cytochrome P450 reductase and glucose 6-phosphatase. However with DEN treatment, microsomal MDA content showed a increasing tendency. Cytochrome P450 content was also significantly increased while microsomal glucose 6-phophatase activity was significantly decreased with DEN treatment. However the activity of NADPH cytochrome P450 reductase was not affected. An interesting finding in this study was that the number and area of hepatic GST-P$^{+}$ foci of rats fed gamma irradiated pork were tended to be decreased by high dose of irradiation, but were not significantly different. These results might imply that the consumption of low dose of gamma irradiated pork does not affect the formation of hepatic GST-P$^{+}$ foci and lipid peroxide and membrane stability.ability.

• Toxicological Research
• /
• 제13권1_2호
• /
• pp.23-27
• /
• 1997

This study was performed to examine the anti-cancer effect of Red Ginseng in the DENGalN-PH-induced hepatic tumor model system in rats. One hundred of male SPF Sprague-Dawley rats(6weeks old) were randomly divided into five groups. Rats in groups 1, 2, 3, and 4 were administered to diethylnitrosamine intraperitoneally 200 mg/kg body weight for the caner initiation. Rats in group 5 were given to saline as a control. On two weeks after cancer initiation, rats in groups 1 and 3 were fed on diet containing 0.01% of acethylaminofiuorene(AAF) which is strong cancer-promotor for 6 weeks, while rats in groups 2 and 4 were fed on water containing 0.05% of phenobarbital which is weak cancer.promotor for 6 weeks. Rats in groups 1 and 2 were treated with diet containing 3% of Red Ginseng for six weeks(from 9th week till 15th week after cancer initiation). Rats in all groups were necropsied time-sequencially at 8, 15, and 36 weeks. The hepatic lesions of rat treated with carcinogens expressed glutathione S-transferase placental form(GST-P) at 8 week. The GST-P positive foci of rats treated with AAF were larger than that of any other rats, while the GST-P positive foci of rats treated with AAF and red ginseng were significantly decreased. This anti-cancer effect of Red ginseng might be involved in the enhacement of natural killer cell activity. To know whether there is direct relationship between Red Ginseng and natural killer cell activity, the activity of natural killer cell was examined after treatment AAF, AAF+Red ginseng and Red ginseng only, respectively. Comparing with natural killer cell activity in AAF-treated group, natural killer cell activity was significantly activated in AAF+ Red ginseng-treated group. This indicated that Red ginseng might enhance natural killer activity after treatment carcinogen in rats. These results suggested that Red ginseng might have a cancer prevention ability by promoting natural killer cell activity during hepatocarclnogenesis.

• 한국식품위생안전성학회지
• /
• 제13권1호
• /
• pp.29-33
• /
• 1998

의약품과 식품을 포함한 자연이나 환경 속에 포함되어 있는 여러 가지 화학물질들은 암 및 돌연변이를 유발할 수 있기 때문에 이런 것들에 의한 유해작용을 줄이려 노력하고 있으나 완전히 없기에는 어려운 현실이다. 따라서 식생활 습관을 개선하거나 식품 내에 존재하는 발암억제물질은 이용하여 암의 발생을 줄이기 위한 연구는 암의 치료제 개발과 더불어 관심의 대상이 되고 있다. 여러 가지 식품 속에 자연적으로 함유된 ellagic acid는 항돌연변이와 발암억제 효과가 있는 것으로 잘 알려져 있다. 따라서 본 실험에서는 단기간에 ellagic acid의 발암 억제 효과를 알아보기 위하여 전암지표효소인 GST-P 양성증식소를 측정하였다. Diethylnitrosamine으로 간장에서 암을 유발하였고 phenobarbital 과 간부분절제술로 암을 촉진시켰으며, ellagic acid를 400과 800ppm 투여군으로 구분하고 투여시기를 달리하여 실험하였다. 실험결과 암이 유발되기 전부터 실험종료까지 ellagic acid 400 ppm 투여군의 동물에서만 발암 억제효과를 관찰 할 수 있었으나, 800ppm 투여군에서는 투여시기에 관계없이 종양억제효과가 나타났다. 따라서 Diethylnitrosamine으로 유발된 간장의 발암은 ellagic acid에 의해 용량 의존적으로 억제됨을 알 수 있었다.