• Toxicological Research
• /
• v.34 no.4
• /
• 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.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1994.04a
• /
• 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.

• Asian-Australasian Journal of Animal Sciences
• /
• v.28 no.8
• /
• pp.1194-1201
• /
• 2015

This study investigated the effect of oxidized soybean oil in the diet of young chickens on growth performance and intestinal oxidative stress, and indices of intestinal immune function. Corn-soybean-based diets containing 2% mixtures of fresh and oxidized soybean oil provided 6 levels (0.15, 1.01, 3.14, 4.95, 7.05, and $8.97meqO_2/kg$) of peroxide value (POV) in the diets. Each dietary treatment, fed for 22 d, had 6 replicates, each containing 30 birds (n = 1,080). Increasing POV levels reduced average daily feed intake (ADFI) of the broilers during d 1 to 10, body weight and average daily gain at d 22 but did not affect overall ADFI. Concentrations of malondialdehyde (MDA) increased in plasma and jejunum as POV increased but total antioxidative capacity (T-AOC) declined in plasma and jejunum. Catalase (CAT) activity declined in plasma and jejunum as did plasma glutathione S-transferase (GST). Effects were apparent at POV exceeding $3.14meqO_2/kg$ for early ADFI and MDA in jejunum, and POV exceeding $1.01meqO_2/kg$ for CAT in plasma and jejunum, GST in plasma and T-AOC in jejunum. Relative jejunal abundance of nuclear factor kappa B ($NF-{\kappa}B$) P50 and $NF-{\kappa}B$ P65 increased as dietary POV increased. Increasing POV levels reduced the jejunal concentrations of secretory immunoglobulin A and cluster of differentiation (CD) 4 and CD8 molecules with differences from controls apparent at dietary POV of 3.14 to $4.95meqO_2/kg$. These findings indicated that growth performance, feed intake, and the local immune system of the small intestine were compromised by oxidative stress when young broilers were fed moderately oxidized soybean oil.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.18
• /
• pp.8411-8418
• /
• 2016

The effect of Eruca sativa seed extract (SE) on nuclear factor kappa B (NF-${\kappa}B$), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels was investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(${\alpha}$)anthracene (DMBA). DMBA increased NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while, decreased glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. After DMBA administration, SE treatment reduced NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and LP. Hence, SE treatment reduced inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC. Analysis revealed that SE has high concentrations of total flavonoids, triterpenoids, alkaloids and polyphenolic compounds such as gallic, chlorogenic, caffeic, 3,4-dicaffeoyl quinic, 3,5-dicaffeoyl quinic, tannic, cinnamic acids, catechin and phloridzin. These findings indicate that SE may be considered a promising natural product from cruciferous vegetables against breast cancer, especially given its high antioxidant properties.

• Biomedical Science Letters
• /
• v.12 no.4
• /
• pp.419-425
• /
• 2006

Phospholipase $C-{\gamma}1\;(PLC-{\gamma}1)$ is an important signaling molecule for cell proliferation and differentiation. $PLC-{\gamma}1$ contains two pleckstrin homology (PH) domains, which are responsible for protein-protein interaction and protein-lipid interaction. $PLC-{\gamma}1$ also has two Src homology (SH)2 domains and a SH3 domain, which are responsible for protein- protein interaction. To identity proteins that specifically binds to PH domain of $PLC-{\gamma}1$, we prepared and incubated the glutathione S-transferase(GST)-fused PH domains of $PLC-{\gamma}1$ with COS7 cell lysate. We found that 90 kDa protein specifically binds to PH domain of $PLC-{\gamma}1$. By matrix-assisted laser desorption ionization time of flight-mass spectrometry, the 90 kDa protein revealed to be heat shock protein (Hsp) $90{\beta}$. Hsp $90{\beta}$ is a molecular chaperone that stabilizes and facilitates the folding of proteins that are involved in cell signaling, including receptors for steroids hormones and a variety of protein kinases. To know whether Hsp $90{\beta}$ affects on $PLC-{\gamma}1$ activity, we performed $PIP_2$ hydrolyzing activity of $PLC-{\gamma}1$ in the presence of purified Hsp $90{\beta}$ in vitro. Our results show that the Hsp $90{\beta}$ dose-dependently inhibits the enzymatic activity of $PLC-{\gamma}1$ and further suggest that Hsp $90{\beta}$ regulates cell growth and differentiation via regulation of $PLC-{\gamma}1$ activity.

• Korean journal of food and cookery science
• /
• v.21 no.5
• /
• pp.599-606
• /
• 2005

The study was carried out to measure the antitumor effect of traditional doenjang (Korean soybean paste) added with Japanese apricot, garlic or ginger. Four kinds of traditional doenjang inhibited significantly the tumor growth in mice injected sarcoma-I80 cells. Especially, traditional doenjang added with ginger (Gi-TD) showed an inhibition of tumor cell activity of 97% by the administration of 1.0 mg/kg methanol extracts. Among Balb/c mouse administered doenjang extracts, the liver weight of mice fed Gi-TD was heavier than that of the group not administered doenjang. However, no difference was found between the control and doenjang administrated groups in weights of body, spleen, kidney and heart. The activity of natural killer (NK) cells was relatively high in mice administrated with the four kinds of doenjang. Particularly, mice administrated with the Gi-TD methanol extracts showed a strong activity of 82.9%. The activity of glutathione S-transferase (GST) in mice administrated with the 4 kinds of doenjang was higher than that of the group not administered with doenjang. In particular, the GST activity was the strongest in the group administrated with Gi-TD. The results suggest that Gi-TD has a strong growth inhibition activity against sarcoma-180 tumor cells.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.1
• /
• pp.117-123
• /
• 2016

Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-${\kappa}B$), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(${\alpha}$) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

• The Journal of Internal Korean Medicine
• /
• v.24 no.1
• /
• pp.55-67
• /
• 2003

Objective : In order to investigate the curative effect of Jucha-whan on the protective liver of guinea pigs induced by $CCl_4$ and d-galactosamine, serum transaminase(GOT, GPT), lactic dehydrogenase(LDH), alkaline phosphatase(ALP), glutathione S-transferase(GST), superoxide dismutase(SOD) were used to measure enzyme activities and lipid peroxide level. Method : The subject animals were divided into 5 groups; a control group(untreated), a subject group(administered with 0.9% Saline solution), a sample I (500mg/kg administered), sample II group (1000mg/kg administered), positive control group(administered with 200mg/kg silymarine). Result : The inhibitory effects on the serum GOT, LDH, ALP, SOD and Lipid peroxide level activities in protective liver of mice induced by $CCl_4$ were noted both in the sample I group and sample II. The inhibitory effects on the serum GPT activities in protective liver of guinea pigs induced by $CCl_4$ were noted in sample II group, but it was not noted in the sample I. The inhibitory effects on the GST activities in protective liver of guinea pigs induced by $CCl_4$ were not noted in both sample I and sample group II. The inhibitory effects on the serum GOT, GPT activities in protective liver of guinea pigs induced by d-galactosamine were noted in both sample I and sample II, but it was not recognizable statistically. The inhibitory effects on the serum LDH activities in protective liver of guinea pigs induced by d-galactosamine were noted in sample II, but it was not noted in sample I group. Conclusion : According to the above results, it is considered that Jucha-whan has treatment effects on liver injury in guinea pigs induced by $CCl_4$ and d-galactosamine. So it is required to study about the actions of mutual relation of medicines and patho-mechanism through experiment.

• Korean Journal of Pharmacognosy
• /
• v.33 no.1 s.128
• /
• pp.5-12
• /
• 2002

This study was performed to evaluate hepatoprotective effect of Daewhang-whangryunhaedok-Tang(DWT) on liver injured rats induced by $CCl_4$ and the acute oral toxicity of it in mice. The activities of serum transaminase(ALT/AST), alkaline phosphatase(ALP) and lactic dehydrogenase (LDH), the levels of serum total cholesterol(TC) and triglyceride(TG), change of liver enlargement, and inhibitory activities of lipid peroxidation, catalase and glutathione-S-transferase(GST) in liver microsome were determined in hepatotoxic rats induced by $CCl_4$ DWT DWT was significantly reduced the serum ALT, AST, ALP, LDH, TC and TG levels. And, the increase of lipid peroxidation, decrease of catalase and GST activities in the liver microsome of $CCl_4$-intoxicated rat were significantly improved by the treatment of DWT. Male and female mice were administered maximum dosages of 5,000 mg/kg b.w. of DWT. After single oral administration of DWT to mice, we observed them daily for 2 weeks. DWT did not induce any toxic signs in the mortalities, clinical signs, body weight changes, and gross necropsy findings of mice. Based on these results, it is concluded that DWT may have the hepatoprotective effect on $CCl_4$ induced hepatotoxicity in rats. Also, DWT may have no side effect and its $LD_{50}$ value may be over 5,000 mg/kg b.w. in mice.

• Biomolecules & Therapeutics
• /
• v.5 no.4
• /
• pp.344-350
• /
• 1997

The purpose of the present study was to produce and characterize a monoclonal antibody against human ${\beta}_2$-adrenergic receptor. Male BALB/c mice were immunized with glutathione S-transferase (GST) fusion protein of the C-terminal portion of the human ${\beta}_2$-adrenergic receptor which was expressed in E.Coli. The immunized splenocytes were fused with myeloma SP2/0-Agl4 cells. The resulting hybridomas were screened for the production of a monoclonal antibody which can recognize human ${\beta}_2$-adrenergic receptor, and then subcloned by limiting dilution. The resulting monoclonal antibody was named as mAb$\beta$CO2. The mono-clonal antibody $\beta$CO2 was determined as IgM subtype and then purified by anti-mouse IgM-agarose affinity chromatography. The results of ELISA, Western blot, and immunocytochemistry showed that mAb$\beta$CO2 recognized human ${\beta}_2$-adrenergic receptor in the ${\beta}_2$-adrenergic receptor-GST fusion protein and human spider-moid carcinoma cell line A431 with highly specific immunoreactivity, The monoclonal antibody $\beta$CO2 may provide useful tools for the study of the $\beta$-adrenergic receptor of human and other species including rats.