• 한국독성학회:학술대회논문집
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• 한국독성학회 2000년도 국제심포지움 및 추계학술대회
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• pp.45-67
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• 2000

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a mutagenic and carcinogenic heterocyclic amino found in cooked meat. The in vivo mutagenicity and hepatocarcinogenicity of MeIQx were examined in mice harboring the lacZ mutation reporter gene ($Muta^{TM}$ Mice) and bitransgenic mice over-expressing the c-myc oncogene. C57B1/$\lambda$lacZ and bitransgenic c-myc (albumin promoter)/$\lambda$lacZ mice were bred and weaned onto an AIN-76 based diet containing $0.06\%$ (w/w) MeIQx or onto control diet. After 30 weeks on diet, only male bitransgenic mice on MeIQx developed hepatocellular carcinoma ($100\%$ incidence) indicating that there was synergism between c-myc over-expression and MeIQx. By 40 weeks, hepatic tumor incidence was $100\%$ ($17\%$) and $44\%$ ($0\%$) in male c-myc/$\lambda$lacZ and C57B1/$\lambda$lacZ mice given MeIQx (or control) diet, respectively, indicating that either MeIQx or c-myc over-expression alone eventually induced hepatic tumors. At either time point, mutant frequency in the lacZ gene was at least 40-fold higher in MeIQx-treated mice than in control mice of either strain. These findings suggest that MeIQx-induced hepatocarcinogenesis is associated with MeIQx-induced mutations. Elevated mutant frequency in MeIQx-treated mice also occurred concomitant with the formation of MeIQx-guanine adducts as detected by the $^{32}P$-postlabeling assay. Irrespective of strain or diet, sequence analysis of the lacZ mutants from male mouse liver showed that the principal sequence alteration was a single guanine-base substitution. Adenine mutations, however, were detected only in animals on control diet. MeIQx-fed mice harboring the c-myc oncogene showed a l.4-2.6-fold higher mutant frequency in the lacZ gene than mice not carrying the transgene. Although there was a trend toward higher adduct levels in c-myc mice, MeIQx-DNA adduct levels were not significantly different between c-myc/$\lambda$lacZ and C57B1/$\lambda$lacZ mice after 30 weeks on diet. Thus, it appeared that factors in addition to MeIQx-DNA adduct levels, such as the enhance rate of proliferation associated with c-myc over-expression, may have accounted for a higher mutant frequency in c-myc mice. In the control diet groups, the lacZ mutant frequency was significantly higher in c-myc/$\lambda$lacZ mice than in 057B1/$\lambda$1acZ mice. The findings are consistent with the notion that c-myc over-expression is associated with an increase in mutagenesis. The mechanism for the synergistic effects of c-myc over-expression on MeIQx hepatocarcinogenicity appears to involve an enhancement of MeIQx-induced mutations.

• BMB Reports
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• 제34권1호
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• pp.90-94
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• 2001

The mutagenic activity of chitosan oligosaccharide and its antimutagenic effect against 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) were investigated using the Salmonella/Ames test. No mutagenic activity was found in the Salmonella typhimurium strains TA 98 and TA 100, either with or without S9 activation. In contrast, chitosan oligosaccharide showed an inhibitory effect on the mutagenic activity of the cooked food mutagen, MeIQx, in the presence of S9. The influence of chitosan oligosaccharide on the genotoxicity of MeIQx was examined using a host-mediated assay in mice. The oligosaccharide was administered for 14 consecutive days (intragastric application at doses of 0.1 or 0.5 g/kg body wt) to mice. S. typhimurium TA 98 was given intravenously before an oral dose of MeIQx (4.5 mg/kg body wt.). The number of $his^+$ revertants were determined from the Ever of mice. The intragastric application of oligosaccharide led to a 47% reduction in the number of mutants induced by MeIQx (p<0.05). These results suggested that chitosan oligosaccharide had antimutagenic properties against MeIQx in vitro and in vivo.

• Journal of Microbiology and Biotechnology
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• 제11권2호
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• pp.346-349
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• 2001

The antimutagenic activity of polysaccharides extracted from soybeans fermented with Agrocybe cylindracea (AC) or Phellinus igniarius (PI) against 2-amino-3,8-dimethylimidaxo[4,5-f]quinoxaline (MeIQx) was examined using a Salmonella/Ames test and host-mediated assay in mice. The polysaccharides from the soybeans fermented with A. Cylindracea and P. igniarius inhibited the mutagenic acitivity of the cooked food mutagen, MeIQx, by 31.2% and 35.3%, respectively. The polysaccharides also inhibited MeIQx genotoxicity in a dose-dependent manner in micel. These results suggest that the polysaccharides from soybeans fermented with A. cylindracea or P. igniarius exhibit antimutagenic properties against MeIQx in vitro and in vivo.

• 한국식품영양과학회지
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• 제27권3호
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• pp.537-542
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• 1998

The present study was performed to elucidate desmutagenic principles from Ecklonia stolonifera extracts against 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine(PhIP) and 2-amino-3,8-dime-thylimidazo[4,5-f]duinoxaline(MeIQx) with Salmonella/mammalian-microsome mutagenicity test. Alginate, phenols, chlorophyll and carotenoids from Ecklonia stolonifera were extracted and their desmutagenicities were assayed. Alginate hydroysates showed desmutagenic activities against PhIP and MeIQx at high level dose. Phenol fractions and bromophenol showed desmutagenic activity of about MeIQx at high level dose. Phenol fractions and bromophenol showed desmutagenic activity of about 90% per 0.5mg against PhIP and MeIQx. Chlorophyllin among chlorophyll derivatives exhibited remarkable desmutagenic activities of 92.9% and 82.7% at 20uM against PhIP and MeIQx, respectively. Carotenoids, such as lutein and $\alpha$-cryptoxanthin isolated from Ecklonia stolonifera exerted also high desmutagenic activity. Major desmutagenic substances from Ecklonia stolonifera are considered to be chlorophyllin, phenols, lutein, $\alpha$-cryptoxanthin and low molecular alginates.

• 한국수산과학회지
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• 제31권4호
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• pp.581-586
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• 1998

해조류 추출물을 이용하여 가열 식품 유래의 돌연변이 유발물질인 PhIP와 MeIQx에 대한 돌연변이원성 억제소재를 개발하기 위하여 연구한 결과, PhIP와 MeIQx에 대한 돌연변이 억제작용은 갈조류가 녹조류 및 홍조류에 비해 우수하였다 특히 갈조류 중에서는 감태, 곰피, 다시마 및 미야베모자반에서 그 효과가 우수하였다. 그 중에서 곰피를 diethyl ether, chloroform, ethyl acetate 및 수용성 획분으로 분획하였을 때, 수용성 획분을 제외한 비극성 획분에서 억제효과가 강하게 나타났는데, ethyl acetate 획분에서 강하였다. 곰피의 ethyl acetate 획분을 Sephadex LH20으로 분획 하여 분리 한 결과, 활성 획 분 A-7은 PhIP에 대하여는 $90\%$/mg 이상, MeIQx에 대하여는 $80\%$/mg의 억제효과를 나타내었고, 207.7 및 232nm에서 흡수파장을 나타내었다.

• 한국축산식품학회지
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• 제31권4호
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• pp.563-569
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• 2011

일상 생활에서 섭취하는 가열한 생선, 육류 등의 고단백질 식품에서는 돌연변이원, 발암가능성 물질인 heterocyclic amine류가 생성된다. 안전성 측면을 고려하고자 백련 잎을 이용한 마리네이드 소스를 첨가하여 쇠고기의 HCAs의 형성억제효과와 돌연변이원성 억제효과를 알아보았다. Ames assay 결과 백련 잎 butanol fraction을 2.0 g 첨가하여 가열한 쇠고기 스테이크에서 61.5%로 높은 돌연변이원성 억제효과를 나타내었지만 용매 별 fraction 첨가군 사이에서는 유의적인 차이를 나타내지 않았다. 가열 전 쇠고기 마리네이드 소스에 식용이 가능한 백련잎 water fraction(2.0, 4.0, 8.0 g)을 첨가한 후 $190^{\circ}C$에서 가열한 결과 MeIQx(2-amino-3,8 dimethylimidazo[4,5-f]-quinoxalin)는 30.9-63.5%, PhIP(2-amino-1-methyl-6-pheny-limidazo[4,5-b]-pyridine)는 31.6-60.7% 억제되었다. $225^{\circ}C$에서의 가열된 쇠고기에서는 MeIQx가 38.1-65.3%, DiMeIQx (2-amino-3,4,8 trimethylimidazo[4,5-f]-quinoxaline)는 36.8-73.9%, PhIP는 33.9- 67.6%의 억제효과를 보였다. 따라서 백련 잎 추출물은 heterocyclic amine류 형성과 돌연변이 원성을 억제하는 효과가 있는 것으로 나타나 고단백질 식품 섭취시 안전성 측면에서 긍정적인 영향을 미칠 것으로 판단된다.

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

• 한국환경성돌연변이발암원학회지
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• 제18권1호
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• pp.26-31
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• 1998

Antimutagenic activity of Saururus chinesis (Lour.) Bail was investigated for food-borne mutagens using S. typhimurium TA98. Methanol extract from Saururus Chinesis (Lour.) Bail was fractionated into hexane, chloroform, ethylacetate and butanol fractions, followed by determination of antimutagenic activity for food-borne mutagenic heterogenic amines (HCA). The hexane fraction exhibited a strong antimutagenic activity for 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQ), 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 3-amino-1-methyl-5H-pyroid[4,3-b]indole acetate (Trp-2-A); however its fraction rather enhanced the bacterial mutagenicity of 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinozaline (4,8-diMeIQx) and 2-amino-3,7,8-trimethyl-3H-imidazo[4,5-f]quinoxline (7,8-diMeIQx). Active principle in the fraction was found to be two major compounds (${\gamma}$-crene B and epi-bicyclosesquiphellandrane) and 6 minor compounds (${\delta}$-caryophyllene, ${\gamma}$-elemene, ${\beta}$-cabebene, ${\delta}$-cadinene, ${\delta}$-selinene, and patchoulene). Modulation effect for the mutagenic activity of the food-borne mutagenic HCA by the fraction might be derived from a cumulative effect of each individual compounds. Hence, this hexane fraction might be use to reduce the production of mutagenic HCA during cooking process of protein-rich foods.

• 한국식품과학회지
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• 제40권4호
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• pp.389-393
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• 2008

양파를 첨가하여 가열 조리한 햄버거 패티의 HCAs 형성과 돌연변이원성에 미치는 영향을 알아보았다. 가열조리 전 햄버거 패티에 양파(2.0, 5.0, 10.0%, w/w)를 첨가한 후 $190^{\circ}C$(프라이팬 표면온도)에서 조리한 경우 MeIQx 형성이 23.3-58.0% 억제되었고 PhIP는 38.9-63.0% 억제되었다. 반면 표면온도를 $225^{\circ}C$로 증가시켜 HCAs 형성억제효과를 측정한 결과 MeIQx는 31.8-44.6%, DiMeIQx는 24.1-39.1%, PhIP는 50.3-70.5%의 억제효과를 보였다. 또한 양파 첨가에 따른 항돌연변이 활성을 측정한 결과 $190^{\circ}C$에서는 43.8-51.2%, $225^{\circ}C$에서는 34.9-48.3%의 수준이었으며 양파 첨가량이 증가할수록 높은 항돌연변이 활성을 보였다. 이러한 결과는 양파에 함유되어 있는 당(glucose, fructose, lactose), flavonoid계 (quercetin 및 그 배당체), thiosulfinate compounds(DADS, DATS, DPDS, DPTS) 등에 의해 Maillard 반응이 억제되었기 때문이며 결과적으로 양파가 HCAs 형성을 억제하고 돌연변이원성을 감소시키는데 효과적임을 알 수 있었다.

• 한국축산식품학회지
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• 제28권5호
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• pp.637-644
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• 2008

식품 중 HCAs을 검출하기 위한 최적 전처리 방법을 확립하기 위해 가열 조리된 돼지고기 패티를 이용하여 서로 다른 4가지 SPE(solid-phase extraction)방법을 비교하였다. 4가지 전처리 방법을 통해 얻은 15가지 HCAs 회수율은 3.0%(방법 A, Tri-P-1)-74.7%(방법A, Tri-P-2)이었다. 그 중 $MeA{\alpha}C$가 평균적으로 73.4%로 가장 높은 회수율을 보였으며 Tri-MeIQx가 15.2%의 가장 낮은 회수율을 보였다. 4가지 전처리 방법 중 방법A와 방법D가 가장 높은 회수율과 검출빈도를 보였으며 방법B와 방법C는 Harman(14.8%)을 제외하고는 전혀 검출되지 않았고 회수율을 구할 수 없었다 발암 가능 물질인 IQ, $A{\alpha}C$, $MeA{\alpha}C$, Glu-P-1, Glu-P-2, MeIQ, MeIQx, PhIP 등을 검출하는 방법에는 방법A(48.7-74.6%)가 4가지 방법 중 가장 유리하다. HCAs는 극성에 따라 polar amines과 less-polar amines으로 구분할 수 있는데 방법A는 less-polar amines검출에 유리하고 방법D는 polar amines검출에 유리하다. 방법A와 방법D의 chromatogram을 비교한 결과 방법A와 방법D 모두 15가지 HCAs가 깨끗하게 분리되었지만 Tri-MeIQx 등을 검출하는데 방법A가 더욱 유리하다. SPE 전처리 방법 및 LC/MS 분석방법에 대한 유효성을 확인하기 위해 LOD(0.2-2.1 ng/mL)와 LOQ(0.8-9.7 ng/mL), 표준 편차(0.2-8.6)를 구하였다.