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AFB₁ 대사에서 phloretion의 이중 활성 효과
임대원,이광,고상상,진효연,은상용,최병민,김복량 圓光大學校 醫科學硏究所 2008 圓光醫科學 Vol.23 No.1
Aflatoxm B₁(AFB₁) is a potent hepatocarcinogen in experimental animals and a hazard to human health in several parts of the world. AFB₁ is activated to its ultimate carcinogenic intermediate, AFB₁-8,9-epoxide, by cytochrome P450(CYP) 1A2 and CYP3A4 in human liver and the intermediate is decomposed by several glutathione S-transferase(GST) including GSTA2, GSTM1 and GSTP1. In this study, we investigated the effects of phloretin on the enzyme systems which are involved in the activation and detoxification of AFB₁. The metabolic intermediate of AFB₁ was measured with HPLC. We found that phloretin could strongly inhibit the activities of CYP 3A4 and CYP1A2 in a dose dependent manner. Phloretin induced the antioxidant-response element(ARE)-mediated gene expression, including GSTs. The expressions of GSTA2, T1, M1, and GSTP1 were induced by 10μM phloretin. The decomposition of AFB₁-8,9-epoxide was measured with GSH conjugating activity of the epoxide. The rate was increased to 1.5 fold when HepG2 cells were treated by 10μM phloretin for 12h. In the mean while, the total GST activitives toward CDNB in HepG2 cells were not changed by the treatment with phloretin. The results demonstrate that phloretin has strong chemopreventive effects against AFB₁ toxicity through the inhibition of AFB₁ activation and induction of GSTs.
Kim, Bok Ryang 圓光大學校 醫科學硏究所 1989 圓光醫科學 Vol.5 No.1-2
LPS로 감각한 비장 임파구의 protein methylase Ⅰ 및 Ⅲ의 비활성은 각각 대조군의 3 및 4배로 증가하였으며, protein methylase Ⅰ은 LPS 처리후 36 시간에서, protein methylase Ⅲ는 72 시간에서 각각 최대의 활성을 보였다. 48 시간 동안의 비장 임파구 배양에서 protein methylase Ⅰ에 의한 arginyl 잔기의 methyl화 반응, protein methylase Ⅲ에 의한 lysyl 잔기의 methyl화 반응, DNA합성, 그리고 polyclonal 항체 형성 반응등이 SF보다 SIBA에 의해 더 저해되었다. SIBA에 의한 억제는 배양기간 중 언제라도 투여한 즉시에 나타났다. 반면 SF의 억제 효과는 배양 초기 12 시간 이내에 첨가해야 만이, 또 투여 후 36 시간이 지나야 저해효과가 보이기 시작했는데 그 후 급격히 증가하여 배양 72 시간 이후부터는 SIBA의 저해 효과보다 더 커져 protein methylase Ⅰ 및 Ⅲ의 in vitor 억제 정도와 일치하였다. 이들의 결과들은 protein methylase Ⅰ 및 Ⅲ가 LPS에 의한 비장 임파구의 면역기능 발현에 밀접하게 관여하고 있음을 시사하고 있다. The induction of protein methylase Ⅰ preceded protein methylase Ⅲ induction in the lipopolysaccharide-induced splenic lymphocyte cultures. The methylation of arginyl and lysyl residues, and the proliferative and polyclonal antibody responses at 48 hr of culture were inhibited more sensitively by SIBA. Regardless of when added, SIBA showed its effects on the responeses immediately after addition. The effects of SF were no longer observed when added later than the first 12 hr in the 48 hr experiment. At 96 hr of exposure, the effects were higher than those of SIBA. The data suggest that the methylation by these enzymes is associated with the immune responses of lymphocytes cultured with lipopolysaccharide.
Kim, Bok-Ryang,Park, Rae-Kil,Kim, Dong-Hyun Korean Society of ToxicologyKorea Environmental Mu 1999 Toxicological Research Vol.15 No.1
2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) is known to induce cytochrome p450 1A1 and to activate c-Src kinase and p21 Ras. This study examined the molecular interactions of adaptor proteins including Shc, Grb2, and Sos in rat primary hepatocytes and their relationship to the induction of CYP1A1 by TCDD. TCDD induced CYP1A1 level and EROD activity in a dose-dependent mode. Sos/Grb2 association isincreased by TCDDㅑㅜ a dose dependent mode. Tyrosine phosphorylated Shc, mainly p152, onloads to Grb2/Sos complex upon TCDD stimulation. The electrophoretic mobility shift of Sos is showed by TCDD. These results indicate that TCDD modulated the molecular interaction features of adaptor compoes proteins including Shc, Grb2, and Cnl in early signaling pathway of TCDD-mediated CYP 1A1 induction of rat primary hepatocyte.
Unscheduled DNA Synthesis Induced by Carcinogens in Primary Culture of Rat Hepatocytes
Kim, Bok-Ryang,Paik, Moon-Kee 圓光大學校 醫科學硏究所 1985 圓光醫科學 Vol.1 No.1
Rat의 1 차간세포 배양에 environmental 발암물질을 첨가하여 간의 DNA에 손상을 준뒤 복구되는 정도를 정량적으로 측정하였다. 즉, CaCl density gradient 을 초원심분리(ultra-centnfuge)로 만들어 DNA를 추출해서 그것에 결합된 [^3H]-thymidine양을 liquid scintillating 측정기로 측정하였다. Direct 발암물질인 MNNG에 의한 손상의 복구는 short patch 형태로 복구가 빨리 일어나고, indirect 발암물질인 Benzo(a) Pyrene에 손상의 복구는 large patch 형태로 복구가 천천히 일어난다. [^3H]-thymidine과 발암물질을 세포에 같이 넣고 UDS을 유도시키는 실험에서 B(a)P에 대한 손상의 복구는 12시간까지 계속해서 증가되었으나, MNNG에 대한 손상의 복구는 3시간안에 급속히 증가된 후 그 수준을 12시간 까지 유지시켰다. 발암물질을 세포에 넣어 2시간 동안 손상을 준후 [^3H]-thymidine을 세포에 첨가하여 UDS을 유도시키는 실험에서 B(a)P에 의한 복구는 실험 시작후 3-6 hr에서 최대를 보였다. 또 MNNG에 대한 실험에서는 0-3 hr에서 최대를 보였다. Indirect 발암물질은 세포내에서 대사가 되어야 DNA에 손상을 입힐수 있어 간세포를 얻은 후 18시간 이내에 실험을 시작해야 그 물질의 DNA와 결합하는 성질을 잘 나타낼수 있었다. Dose-response 실험에서는 MNNG는 10^-4M에서 B(a)p는 10^-5M에서 최대값을 얻었다. The ability of direct and pro-carcinogens to induce unscheduled DNA synthesis(UDS) in primary culture of hepatocytes was examined. Hepatocytes were isolated from adult male rats with collagenase perfusion technique and maintained in short-term monolayer culture on collagen-coated plates in serum free modified Waymouth's medium. Incorporation of [^3H]-thymidine into DNA in the presence of hydroxyurea was used to measure UDS. N-Methyl-N'-nitro-N-nitrosoguanidine(MNNG) which elicit a "short-patch" type of DNA repair and benzo(a) pyrene (B(a)P) which result in a "long-patch" type of DNA repair were used as standard carcinogens to show repair patterns. In continuous labelling experiments, UDS induced by B(a)P was increased linearly for 12hr in cultures, but that of
Kim, Bok-Ryang,Park RaeKil,Kim, Dong-Hyun 원광대학교 생명공학연구소 2000 생명공학연구소보 Vol.7 No.1
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce cytochrome P450 1A1 and to activate c-Src idnase and p21 Ras. This study examined the molecular interactions of adaptor proteins including Shc, Grb2, and Sos in rat primary hepatocytes and their relationship to the induction of CYP1A1 by TCDD. TCDD induced CYP1A1 leverland EROD activity in a dose-dependent mode. Sos/Grb2 association is increased by TCDD in a dose dependent mode. Tyrastne phospharylated. Shc. mainly p52, onloads to Grb2/Sos complex upon TCDD stimulation. The electrophoretic mobility shift of Sos is showed by TCDD. These results indicate that TCDD modulates the molecular interaction features of adaptor complex proteins including Shc. Grb2, Sos and Cbl in early signaling pathway of TCDD-mediated CYP1A1 induction of rat primary hepatocytes.
Mechanism of covalent adduct formation of aucubin to proteins
Kim, Dong-Hyun,Kim, Bok-Ryang,Kim, Ji-Yeon,Jeong, Yo-Chan 원광대학교 생명공학연구소 2001 생명공학연구소보 Vol.8 No.1
The iridoid glucoside aucubin can irreversibly bind to proteins through the formation of its aglycone. In view of a possible involvement of these protein adducts in the toxicity of aucubin, we investigated the mechanism of binding of aucubin to proteins. [³H]aucubin in itself did not result in binding e protein whereas it covalently bound to rat serum albumin as a function of exposure time and dose in the presence of β-glucosidase. The rate and extent of protein binding were significantly increased in the presence of the imine-trapping agent sodium cyanide. Oral administration of [³H]aucubin to rats showed that the total radioactivity in plasma remained at a similar level for up to 6 h once peak level was reached, suggesting that a considerable amount of radioactivity might be covalently associated with plasma proteins. The levels of radioactivity in the liver and kidney after oral dosing were higher than those after i.v. dosing. These results indicate that the open-chain aglycone of aucubin can form an imine bond with a nucleophilic site of the protein and these irreversible bindings may partially contribute to its biological and toxic effects. ⓒ 2000 Elsevier Science Ireland Ltd. All rights reserved.