• Archives of Pharmacal Research
• /
• v.27 no.8
• /
• pp.857-862
• /
• 2004

Naringenin, dietary flavonoid, is antioxidant constituents of many citrus fruits. In the present study, we investigated the effect of naringenin on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible CYP1 A 1 gene expression in mouse hepatoma Hepa-1c1c7 cells. Naringenin alone did not affect CYP1A1-specific 7-ethoxyresorufin O-deethylase (EROD) activity. In contrast, the TCDD-inducible EROD activities were markedly reduced upon concomitant treatment with TCDD and naringenin in a dose dependent manner. TCDD-induced CYP1A1 mRNA level was also markedly suppressed by naringenin. A transient transfection assay using dioxin-response element (DRE)-linked luciferase and electrophoretic mobility shift assay revealed that naringe-nin reduced transformation of the aryl hydrocarbons receptor(AhR) to a form capable of specif-ically binding to the DRE sequence in the promoter of the CYP1A1 gene. These results suggest the down regulation of the CYP1A1 gene expression by either naringenin in Hepa-1c1c7 cells might be antagonism of the DRE binding potential of nuclear AhR.

• The Korean Journal of Physiology and Pharmacology
• /
• v.10 no.6
• /
• pp.349-354
• /
• 2006

The aromatic hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the biological and toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related chemicals. The application of recombinant reporter plasmid such as the firefly luciferase gene has proven to be a very effective method to detect these chemicals. The bioassay system, CALUX, is sensitive in directly detecting AhR-agonists from a variety of environmental and biologic materials. However, responses of the AhR-dependent bioassays are dependent on the cell types used. Thus, we developed a sensitive bioassay using the recombinant mouse hepatoma cell (Hepa1c1c7) for the determination of dioxins. The recombinant cell line was stably transfected with firefly luciferase reporter gene (pGudLuc1.1). The transfected cells showed the highest induction of luciferase activity at 4.5 hr and a decrease beyond this time point. The system showed the highest sensitivity of detection ever reported. Upon TCDD exposure cells showed 2 fold increase at 10 pM and 7 fold increase at 100 pM, respectively. The passage number after the transfection played an important role in the sensitivity. The increase of passage number tended to increase the sensitivity of the cells up to 15. The media without phenol red showed a higher induction rate than with phenol red, suggesting the preferable use of phenol red-free media for the bioassay. Since each of the assays has unique characteristics that make them suitable for some screening applications and not others, development of sensitive bioanalytical methods based on a variety of cellular systems in a key to the successful determination of dioxins. The bioassay system developed in this study will contribute to further development of successful screening the AhR agonists among the environmental mixture. In addition, the rapid and sensitive nature of this cellular system can be applied as a valuable tool to screen the dioxin-like moieties among the prodrugs at the initial stage, thereby expediting the new drug discovery.

• Journal of Ginseng Research
• /
• v.30 no.3
• /
• pp.112-116
• /
• 2006

To investigate the protective effect of saponin from red ginseng extract, 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD) was exposed to female guinea pigs and then femur weights was measured. Forty eight female guinea pigs ($820{\pm}25\;g$) were divided into 6 groups. Normal control group (NC) received vehicle and saline; only TCDD-treated group (TT) received TCDD ($5.0\;{\mu}g/kg$, single dose) intraperitoneally; pretreated group of saponin 10 (PE 10) received 10 mg/kg of saponin i.p. for 4 weeks from 1 week before TCDD-exposure; pretreated group of saponin 20 (PE 20) also received 20 mg/kg of saponin i.p. for 4 weeks from 1 week before TCDD-exposure. While, post-treated group of saponin 10 (CE 10) received 10 mg/kg of saponin i.p for 3 weeks after TCDD-exposure. Post-treated group of saponin 20 (CE 20) received 20 mg/kg saponin i.p for 3 weeks after TCDD-exposure. Body weight of TT group was significantly decreased after TCDD-exposure. However, body weight in all saponin-treated groups increased throughout the experimental period, although the increasing rate was slower than that of NC group. Body weights of PE 10 and 20 groups showed more higher increase than those of CE groups during the experimental period. Decrease of femur weights in female guinea pigs by TCDD intoxification was significantly recovered by the saponin treatment. Decrease of $Ca^{2+}$ level of femurs in female guinea pigs exposed TCDD also recovered by the treatment of saponin from red ginseng extract. Especially, PE20 group showed the highest increase of the $Ca^{2+}$ level in femur among the saponin treated groups. These results suggest that ginseng saponin might be a useful protective agent against femur damage caused to decrease of $Ca^{2+}$ by TCDD.

• Toxicological Research
• /
• v.14 no.4
• /
• pp.587-594
• /
• 1998

In order to understand the mechanism if the regulation of CYP 1A1 gene expression and ethoxyresorufin deethylase (EROD) activity in ex vivo system, we have studied the action of TCDD and 3MC in the isolated perfused female rat liver. CYP1A1 mRNA level and EROD activity were measured in rat liver that was isolated and perfused with various chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3MC), 17$\beta$-estradiol (E$_2$), morin. TCDD or 3MC alone perfusion into female rat liver resulted in increase of CYP 1A1 mRNA level and the magnitude of stimulation was six times higher with TCDD treatment than 3MC treatment. However E$_2$ perfusion into female rat liver showed inhibition of CYP 1A1 mRNA level. When 10$^{-8}$ M E$_2$ was administered concomitantly with either 10$^{-9}$ M TCDD or 10$^{-9}$ M 3MC, stimulated CYP 1A1 mRNA by either TCDD or 3MC was inhibited. Morin was examined for its effects on CYP 1A1 mRNA level and result was similar to that was observed with estrogen. EROD activity was also stimulated with either TCDD or 3MC perfusion, and the magnitude of EROD stiumlation was smaller than that of CYP 1A1 mRNA stimulation in response to TCDD or 3MC perfusion. Unlike CYP1A1 mRNA level, stimulation of EROD activity was greater with 3MC than TCDD. Concomitant perfusion either E$_2$ or morin with TCDD or 3MC inhibited 3MC perfusion or TCDD perfusion stimulated EROD activity. These data suggested that TCDD and 3MC might act diffrently in terms of regulation of CYP 1A1 gene expression in rat liver.

• Proceedings of the Ginseng society Conference
• /
• 1998.06a
• /
• pp.300-311
• /
• 1998

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the most notorious toxic environmental pollutants, induces various toxic effects in many organs including testes and is regarded as an endocrine disruptor. Korean ginseng, on the other hand, has been well known for its preventive effects on lox- ins, diabetes melltus and hyperlipidemia. We investigated, histopathologically, the effect of Korean Red ginseng water extract (KR-WE) on guinea pig testes damaged by TCDD. Ninety guinea pigs were divided into 6 groups: normal control (NC) group received vehicle and saline; TCDD,1191kg b.w., was administered intraperitoneally to the single dose TCDD-treated (77) group; 100 mghg b.w.16 and 200mg1kg b.w./d KR-WE were injected intraperitoneally to the preventive groups (PIOO and P2OO, respectively) for 28 days from 1 week before TCDD injection, and to the therapeutic groups (CIOO and C2OO, respectively) for 14 days since 1 week after TCDD administration. Increment of body weight was retarded to a larger extent by TCDD. Moreover, body weight of the 77 group decreased significantly 7 days after TCDD exposure, while that of preventive groups kept increasing. Decrease in body weight was not observed in KR-WE-treated groups. Weight decrease in testes caused by TCDD was remarkably protected by KR-WE. Testicles in 77 group displayed decreased tubular size and maturation arrest at the primary or secondary spermatocyte stage. On the other hand, maturation arrest in germ cells by TCDD was improved in KR-WE treated groups. Almost complete protection of the testes was observed in PIOO and P2OO groups. In addition, the therapeutic effect was noticed in C 100 and C2OO groups. These results provided strong evidence that Korean Red ginseng might be a useful agent for the prevention and treatment of testicular damage induced by environmental pollutants.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.18 no.5
• /
• pp.1410-1417
• /
• 2004

To evaluate effect of Gamimajeonojahwan(GMOH) water extract on sexual functions, we orally administered GMOH exract(1,100㎎/㎏) for four weeks in male rats impaired by 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) and ketoconazole(KZ). And we investigated the sexual behaviors such as mount latency, mount frequency, intromission latency, intromission frequency, ejaculation period and ejaculation latency. Serum testosterone concentrations also are evaluated in GMOH-and/or vehicle-treated male rats. The results were obtained as follows: GMOH inhibited the increase of intromission latency by TCDD in male rats. GMOH inhibited the decrease of intromission frequency by TCDD in male rats. GMOH inhibited the increase of ejaculation latency by TCDD in male rats. GMOH inhibited the decrease of serum testosterone concentration by TCDD in male rats. GMOH inhibited the decrease of serum testosterone concentration by KZ in male rats. These results suggest that GMOH water extract is active in improving sexual functions and protecting a decrease of testosterone concentrations induced by TCDD and KZ in male rats.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.119.2-119.2
• /
• 2003

Exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a variety of biological and toxicology effects, most of which are mediated by aryl hydrocarbon receptor (AhR). The ligand-bound AhR as a heterodimer with AhR nuclear translocator (ARNT) binds to its specific DNA recognition site, the dioxin-responsive element (DRE), and it results in increased transcription of CYP1A1 gene. Retinoic acid (RA) regulates the transcription of various genes for several essential functions through binding to two classes of nuclear receptors, the retinoic acid receptor (RAR) and retinoid X receptor (RXR). (omitted)

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2001.10a
• /
• pp.186-186
• /
• 2001

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that activates the aryl hydrocarbon receptor (AhR) and disrupts multiple endocrine signaling pathways by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene transcription. And TCDD-mediated gene transactivation via the AhR has been shown to be dependent upon estrogen receptor (ER) expression in human breast cancer cells.(omitted)

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2003.10b
• /
• pp.136-136
• /
• 2003

Exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a variety of biological and toxicology effects, most of which are mediated by aryl hydrocarbon receptor (AhR). The ligand-bound AhR as a heterodimer with AhR nuclear translocator (ARNT) binds to its specific DNA recognition site, the dioxin-responsive element (DRE), and it results in increased transcription of CVP1A1 gene.(omitted)

• Proceedings of the Korean Society of Veterinary Pathology Conference
• /
• 2003.10a
• /
• pp.46-46
• /
• 2003

Polychlorinated dibenzo-p-dioxins (PCDDs) are widespread, persistant, and highly toxic environmental pollutants. TCDD is the most potent congener among PCDDs and the most thoroughly investigated model compound of this class of chemicals. These compounds elicit a variety of common biochemical and toxic response, including specific binding to the cytosolic AHR [1] and induces a variety of biological response ranging from induction of cytochrome P-450 1A (CYP1A) to liver damage and cancer [2]. This study was carried out to investigate the protective effects of YCY, extract of a cricket, Gryllus bimaculatus, on hepatotoxicity in 6-week-old SD rat exposured to TCDD (omitted)