• 한국잡초학회지
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• 제18권4호
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• pp.333-340
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• 1998

Primisulfuron 또는 Imazethapyr와 Cytochrome P-450 저해제인 PBO의 혼합처리가 옥수수의 생장 및 ALS효소 활성에 미치는 영향을 조사한 결과는 다음과 같다. 1. Pioneer 3751 IR은 Primisulfuron과 Imazethapyr에 Imazethapyr에 높은 내성을 보인 반면, Pioneer 3751과 찰옥 2호는 감수성을 보였다. 2. Pioneer 3751 IR은 Primisulfuron과 PBO혼합처리에서 높은 저항성을 나타내어 PBO혼합처리에 따른 영향은 적었으나 Pioneer 3751,수원 118호와 찰옥 2호는 PBO혼합처리에 따라 생장 저해가 PBO무처리에 비해 높게 나타났다. 3. Pioneer 3751 IR의 생장은 Imazethapyr와 PBO 혼합처리에 따른 영향은 적었으며 Pioneer 3751과 수원 118호, 찰옥 2호는 생장저해가 심하였으나 PBO혼합처리 에 따른 약해 상승작용은 크지 않았다. 4. ALS효소 활성은 Prirnisulfuron은 $0.01{\mu}M$에서부터, 그리고 Imazethapyr는 $1{\mu}M$에서부터 Pioneer 3751 IR 품종을 제외한 3품종에서 현저하게 억제되었으며, Primisulfuron과 PBO혼합처리에 의하여 Pioneer 3751 IR과 Pioneer 3751에서는 활성저해가 더 크게 나타났고 수원 118호와 찰옥 2호에서는 차이가 없었으며, Imazethapyr와 PBO의 혼합처리에서는 4품종에서 모두 약간 억제되었다.

• 한국식품영양과학회지
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• 제36권4호
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• pp.411-418
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• 2007

솔잎 열수추출물이 카드뮴으로 유도한 흰쥐의 산화적 손상에 미치는 영향을 살펴보고자 체중 kg당 5mg의 카드뮴$(CdCl_2)$을 매주 1회 경구투여하였다. 솔잎은 매일 일정시각에 체중 kg당 1.26g수준이 되도록 4주간 경구투여 사육한 결과 카드뮴과 솔잎 열수추출은 체중에는 영향을 미치지 않았으며 솔잎 열수추출물은 식이섭취량을 감소시켰다. 체중 100g당 간조직 무게는 카드뮴 대조군이 정상군에 비하여 유의적으로 증가하였으며 솔잎 열수추출물은 간조직 무게를 감소시키는 경향이었다 혈장 중의 AST와 ALT활성은 카드뮴 투여에 의해 유의적으로 증가되었으나 솔잎 열수추출물에 의해 ALT활성이 카드뮴 대조군에 비하여 유의적으로 감소되었다. 혈장 알부민 함량은 실험군간의 차이가 없었으나 크레아티닌 함량은 솔잎 열수추출물 급여시 낮았다. 카드뮴 투여시 간조직의 CYP함량은 유의적으로 감소되었으며 솔잎 열수추출물에 의한 영향은 없었다. 한편 XO와 ADH활성은 솔잎 열수추출물군이 정상군과 카드뮴 대조군에 비하여 유의적으로 높았다. 또한 카드뮴 투여에 인해 유의적으로 높아진 SOD, MAO, CAT 및 GSH-Px 활성도는 솔잎 열수추출물에 의해 정상수준으로 회복되었다. 간조직 중의 글루타티온 함량은 솔잎 열수추출물 급여에 의한 차이가 발견되지 않았으나 MDA함량은 솔잎 열수추출물 급여군에서 카드뮴 대조군에 비하여 유의적인 감소를 보임으로써 카드뮴에 의해 유도된 지질과산화가 솔잎 열수추출물 급여로 개선될 수 있음을 제시한다.

• 한국임상약학회지
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• 제17권1호
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• pp.13-18
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• 2007

Theophylline은 methylxanthine계열 기관지확장제중 가장 강력하며 기관지 천식이나 만성 폐쇄성 호흡기 질환환자에서 사용된다. Theophylline은 치료지수가 5-20 mg/L로 매우 좁은 치료지수를 갖는 약물이다. Cimetidine과 theophylline은 주로 간에 존재하는 cytochrome P450 (CYP) 효소에 의해 대사되며 theophylline은 유전적 다형성이 보고된 바있는 CYP1A2에 의해 대부분 대사된다. 본 연구는 theophylline의 약동학에 미치는 cimetidine의 영향을 평가하고 CYP1A2 유전적 다형성의 영향유무를 검증하였다. 8명의 건강한 비흡연자인 한국인 자원자를 모집하여 공개, 2기 교차시험을 실시하였다. 8명의 자원자에게 1기 시험의 첫날 100 mg의 aminophylline을 경구로 단회 투여하였으며 약물투여 후 36시간까지 채혈하여 혈장을 보관하였다. 공혈장 채취를 위해 채혈한 혈액중 일부를 가지고 유전자형 검색을 실시하였다. 1주일의 휴약기를 거친 후 2기 시험을 진행하였다. 2기 시험의 첫날 같은 용량의 aminophylline과 200 mg의 cimetidine을 같이 경구로 단회 투여하였다. 혈장 중 theophylline농도는 고성능 액체 크로마토그래피를 이용하여 측정하였으며 1기와 2기 시험에서 각종 약동학적 경수를 컴퓨터를 이용하여 계산하였다. 8명의 자원자에서 PCR-RFLP를 이용하여 유전자형 검색을 실시하였다. 8명(남자 4명, 여자 4명)의 자원자에서 약물과 관련한 약물이상 반응은 시험기간동안 발생하지 않았다. 약동학적 분석에서 theophylline의 혈장 농도 곡선하 면적(AUC)와 최고혈중농도($C_{max}$)가 cimetidine과 theophylline을 동시에 투여하였을 때 통계적으로 유의하게 증가하였으며 경구 청소율(CL/F)은 유의하게 감소하였다. 8명의 CYP1A2 유전자형 검색에서 돌연변이 유전자형은 발견하지 못하였으며 CYP1A2*1C 유전자형 검색에서 모두 (G/G) homozygote였으며 CYP1A2*1F 유전자형 검색에서는 5명이 (A/A) homozygote이고 3명이 (A/C) heterozygote였다. 따라서 theophylline대사에 CYP1A2유전자형에 따른 대사능의 차이는 관찰할 수 없었다. 이상의 결과를 요약하면 theophylline의 약동학은 cimetidine에 의해 유의한 차이를 보였으며 CYP1A2유전자형에 따른 영향은 관찰할 수 없었다. CYP1A2유전자형에 따른 생체내 대사능을 관찰하는 실험이 향후 이루어 져야 할 것으로 사료된다.

• 생물정신의학
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• 제18권2호
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• pp.95-100
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• 2011

Objectives To evaluate the drug interactions between aripiprazole and haloperidol, authors investigated plasma concentrations of those drugs by genotypes. Method Fifty six patients with a confirmed Diagnostic and Statistical Manual of Mental Disorders 4th edition diagnosis of schizophrenia were enrolled in this eight-week, double blind, placebo-controlled study. Twenty-eight patients received adjunctive aripiprazole treatment and twenty-eight patients received placebo while being maintained on haloperidol treatment. Aripiprazole was dosed at 15 mg/day for the first 4 weeks, and then 30 mg for the next 4 weeks. The haloperidol dose remained fixed throughout the study. Plasma concentrations of haloperidol and aripiprazole were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline, week 1, 2, 4 and 8. $^*1$, $^*5$, and $^*10$ B alleles of CYP2D6 and $^*1$ and $^*3$ alleles of CYP3A5 were determined. The Student's T-test, Pearson's Chi-square test, Wilcoxon Rank Sum test and Logistic Regression analysis were used for data analysis. All tests were two-tailed and significance was defined as an alpha < 0.05. Results In the frequency of CYP2D6 genotype, $^*1/^*10$ B type was most frequent (36.5%) and $^*1/^*1$ (30.8%), $^*10B/^*10B$ (17.3%) types followed. In the frequency of CYP3A5 genotype, $^*3/^*3$ type was found in 63.5% of subjects, and $^*1/^*3$ type and $^*1/^*1$ were 30.8% and 5.8% respectively. The plasma levels of haloperidol and its metabolites did not demonstrate significant time effects and time-group interactions after adjunctive treatment of aripiprazole. The genotypes of CYP2D6 and 3A5 did not affect the plasma concentration of haloperidol in this trial. No serious adverse event was found after adding aripiprazole to haloperidol. Conclusion No significant drug interaction was found between haloperidol and aripiprazole. Genotypes of CYP2D6 and 3A5 did not affect the concentration of haloperidol after adding aripiprazole.

• Molecular & Cellular Toxicology
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• 제5권1호
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• pp.32-43
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• 2009

Acetaminophen (APAP) overdose is known to cause severe hepatotoxicity mainly through the depletion of glutathione. In this study, we compared the cytotoxic effects of APAP on both a normal murine hepatic cell line, BNL CL.2, and its SV40-transformed cell line, BNL SV A.8. Gene expression profiles for APAP-treated cells were also obtained using microarray and analyzed to identify differences in genes or profiles that may explain the differences of susceptibility to APAP in these cell lines. These two cell lines exhibited different susceptibilities to APAP (0-$5,000{\mu}M$); BNL SV A.8 cells were more susceptible to APAP treatment compared to BNL CL.2 cells. A dose of $625{\mu}M$ APAP, which produced significant differences in cytotoxicity in these cell lines, was tested. Microarray analysis was performed to identify significant differentially expressed genes (DEGs) irrespective of APAP treatment. Genes up-regulated in BNL SV A.8 cells were associated with immune response, defense response, and apoptosis, while down-regulated genes were associated with catalytic activity, cell adhesion and the cytochrome P450 family. Consistent with the cytotoxicity data, no significant DEGs were found in BNL CL.2 cells after treatment with $625{\mu}M$ APAP, while cell cycle arrest and apoptosis-related genes were up-regulated in BNL SV A.8 cells. Based on the significant fold-changes in their expression, a genes were selected and their expressions were confirmed by quantitative real-time RT-PCR; there was a high correlation between them. These results suggest that gene expression profiles may provide a useful method for evaluating drug sensitivity of cell lines and eliciting the underlying molecular mechanism. We further compared the genes identified from our current in vitro studies to the genes previously identified in our lab as regulated by APAP in both C57BL/6 and ICR mice in vivo. We found that a few genes are regulated in a similar pattern both in vivo and in vitro. These genes might be useful to develop as in vitro biomarkers for predicting in vivo hepatotoxicity. Based on our results, we suggest that gene expression profiles may provide useful information for elucidating the underlying molecular mechanisms of drug susceptibility and for evaluating drug sensitivity in vitro for extrapolation to in vivo.

• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6101-6104
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• 2012

Background: Breast cancer accounts about one million from total annual ten million new diagnosed cases of neoplasia worldwide and is the main cause of death due to cancer in women. Tamoxifen is the most popular selective estrogen receptor modulator used in anti estrogen treatments. Tamoxifen must be converted into its metabolite endoxifen for biologic effects; this conversion process is catalysed by highly polymorphic cytochrome P450 2D6 (CYP2D6). This study surveyed copy number variation of the CYP2D6 gene and its possible correlation with Tamoxifen resistance in breast cancer patients. Methods: This case control study was performed on samples taken from 79 patients with breast cancer who used tamoxifen in Yazd and Tehran Cities, Iran. Real time reactions were conducted for 10 healthy samples using the comparative $C_t$ (Cycles threshold) method, each pair of genes being compared and samples with ratios around 1 were taken as control samples. Proliferation reactions were done by Real-Time PCR ABI Prism 7500. All registered data were transformed into SPSS 15 program and analyzed. Results: Efficiency of PCR for both CYP2D6 and ALB genes was 100%. From all 23 drug resistant patients 21.7% had one copy, 47.8% two copies and 30.4% had three copies. Also from all 56 drug sensitive patients, 26.8% had one copy, 51.8% two copies and 21.4% had three copies. The percentage of patients with one and two copies was similar between two groups but patients with three copies were more likely to belong to the drug resistant group more. Odd ratios for one and two copies were 0.759 and 0.853 respectively, indicating possible protective effects while that for three copies was 1.604. Conclusions: Based on our study there is no significant link between CYP2D6 gene copy numbers and tamoxifen resistance in women with breast cancer. But more studies considering other influencing factors appear warranted.

• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6505-6510
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• 2012

Background: CYP2E1 encodes an enzyme which is mainly involved in bioactivation of potential carcinogens such as N-nitrosamines. Polymorphisms in the gene have been reported to be associated with cancer. The aim of this study was to evaluate genotype distributions and allele frequencies of five CYP2E1 polymorphisms in Iran Materials and Methods: Two hundred healthy individuals of an Iranian population from the southwest were included in this study. PCR-restriction fragment length polymorphism and Tetra-ARMS PCR methods were applied for CYP2E1 genotyping. Results: The allele frequencies for $^*5B$, $^*6$, $^*7B$, $^*2$, and $^*3$ were calculated to be 1.5%, 16%, 28.5%, 0%, and 2.75% respectively. Results of this study showed that no significant differences in genotype and allele frequencies of five single nucleotide polymorphisms with respect to the gender and tribes. The chi-square test showed that the genotype frequencies of $CYP2E1^*5B$ were similar to Caucasians, but the distribution of $CYP2E1^*6$ genotypes was similar to Asians. The frequencies of $CYP2E1^*2$ (0%) and $CYP2E1^*3$ (2.75%) alleles were within the range for Caucasians and Orientals. In the case of $CYP2E1^*7B$, the data werelimited. Accordingly, the results were only compared with Europeans and the comparison showed significant differences. Conclusions: In conclusion, ethnic and geographic differences may explain discrepancies in the prevalence of CYP2E1 polymorphisms.

• 한국응용곤충학회지
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• 제35권3호
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• pp.254-259
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• 1996

Yumenoshima III 집파리 계통을 ethyl fenitrothion으로 30세대 도태시킨 EF-30 계통에 있어서의 parathion 저항성 메카니즘을 생화학적으로 조사하였다. 아세틸콜린에스테라제 저해활성은 저항성계통과 감수성 SRS 계통간에 커다란 차이를 보여 이 효소의 감수성 저하가 저항성의 주료 메카니즘으로 작용하고 있음을 알 수 있었다. 양 계통에 있어서의 parathion과 paraoxon의 in vitro 분해활성은 미크로좀 및 수용성 분획과 관련이 있으며, 각각 NADPH와 glutathione을 필요로 하였다. 저항성계통은 감수성계통에 비하여 GSH S-transferase 활성이 높아 이 효소가 저항성 메카니즘에 중요한 역할을 하고 있는 것으로 추정되었다. 저항성계통은 parathion에 대하여 101,487배, ethyl parathion에 대하여 25,914배의 저항성비를 나타내어 parathion이 GSH S-transferase의 기질로 작용하고 있음을 알 수 있었다. 이상의 결과로부터 EF-30 계통에 있어서의 저항성 메카니즘에는 수종의 요인이 관여하여 parathion에 대하여 높은 저항성을 나타냄을 알 수 있었으나, 이들 요인이외에 타 요인의 관여를 배제할 수 없었다.

• 약학회지
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• 제40권6호
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• pp.727-733
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• 1996

2-(Allylthio)pyrazine is effective in selectively suppressing constitutive and inducible expression of cytochrome P450 2E1. The effect of 2-(allylthio)pyrazine against potentiat ed chemical injury was studied in rats. Vitamin-A pretreatment of rats substantially increased carbon tetrachloride hepatotoxicity, as supported by an ~4-fold increase in serum alanine aminotransferase (ALT) activity. Concomitant pretreatment of rats with 2-(allylthio)pyrazine at the daily dose of 200mg/kg resulted in a 76% decrease in vitamin-A-potentiated hepatotoxicity, which supported the possibility that 2-(allylthio)pyrazine protects the liver against chemical-induced hepatic injury by the mechanism associated with Kupffer cell inactivation. Pyridine pretreatment caused substantial enhancement in carbon tetrachloride hepatotoxicity. 2-(Allylthio)pyrazine treatment of rats reduced the pyridine-potentiated toxicity in a dose-dependent manner. Animals treated with both pyridine and 2-(allylthio)pyrazine prior to intoxicating dose of CCl$_4$ resulted in 85% and 47% decreases in pyridine-increased triglycerides and cholesterol levels in the liver. The protective effect of 2-(allylthio)pyrazine on the DNA strand breakage induced by benzenetriol was assessed by measuring the conversion of supercoiled ${\Phi}x$-174 DNA to the open relaxed form. 2-(Allylthio)pyrazine blocked the benzenetriol-induced conversion of supercoiled DNA to open circular form in a dose-dependent manner. The presence of 2-(allylthio)pyrazine at the doses from I to 10mM in the incubation mixture containing 5 ${\mu}$M benzenetriol completely protected benzenetriol-induced DNA strand breakage with the EC50 for the 2-(allylthio)pyrazine blocking being noted as ~220 ${\mu}$M, whereas allyl disulfide exerted protecting effect at relatively high concentrations (i.e. ~850 ${\mu}$M), suggesting that 2-(allylthio)pyrazine effectively scavenges the reactive oxygen species. These results provide evidence that 2-(allylthio)pyrazine blocks vitamin A- or pyridine-potentiated CCl$_4$ hepatotoxicity and that the agent is active in protecting DNA by scavenging the reactive oxygen species.

• 한국작물학회:학술대회논문집
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• 한국작물학회 2017년도 9th Asian Crop Science Association conference
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• pp.24-24
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• 2017

Heavy metals at toxic levels have the capability to interact with several vital cellular biomolecules such as nuclear proteins and DNA, leading to oxidative stress in plants. The present study was performed to explore the metal tolerance mechanism in Sorghum seedling. Morpho-physiological and metal ions uptake changes were observed prominently in the seedlings when the plants were subjected to different concentrations of $CuSO_4$ and $CdCl_2$. The observed morphological changes revealed that the plants treated with Cu and Cd displayed dramatically altered shoot lengths, fresh weights, and relative water content. In addition, the concentration of Cu and Cd was markedly increased by treatment with Cu and Cd, and the amount of interacting ions taken up by the shoots and roots was significantly and directly correlated with the applied level of Cu and Cd. Using the 2-DE method, a total of 24 and 21 differentially expressed protein spots from sorghum leaves and roots respectively, 33 protein spots from sorghum leaves under Cd stress were analyzed using MALDI-TOF/TOF MS. However, the over-expression of GAPDH plays a significant role in assisting Sorghum bicolor to attenuate the adverse effects of oxidative stress caused by Cu, and the proteins involved in resistance to stress helped the sorghum plants to tolerate high levels of Cu. Significant changes were absorbed in the levels of proteins known to be involved in carbohydrate metabolism, transcriptional regulation, translation and stress responses. In addition, the up-regulation of glutathione S-transferase and cytochrome P450 may play a significant role in Cd-related toxicity and stress responses. The results obtained from the present study may provide insights into the tolerance mechanism of seedling leaves and roots in Sorghum under heavy metal stress.