Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis

Kim, Sang-Heon,Kim, Sang-Hoon,Bahn, Joon-Woo,Kim, Yoon-Keun,Chang, Yoon-Seok,Shin, Eun-Soon,Kim, Youn-Seup,Park, Jae-Seuk,Kim, Bo-Hyung,Jang, In-Jin,Song, Junghan,Kim, Seung-Hyun,Park, Hae-Sim,Min, Ky Future Medicine 2009 Pharmacogenomics Vol.10 No.11

<P>AIMS: Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis. MATERIALS & METHODS: We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls. RESULTS: Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types. CONCLUSION: These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.</P>

<i>ABCC2</i> Haplotype is Associated With Antituberculosis Drug-Induced Maculopapular Eruption

Kim, Sang-Heon,Jee, Young-Koo,Lee, Jae-Hyung,Lee, Byoung-Hoon,Kim, Youn-Seup,Park, Jae-Seuk,Kim, Sang-Hoon The Korean Academy of Asthma, Allergy and Clinical 2012 Allergy, Asthma & Immunology Research Vol.4 No.6

<P>Genetic variants in ATP-binding cassette (ABC) transporter genes are associated with increased susceptibility to adverse drug reactions. We hypothesized that genetic variant ABC transporters (<I>ABCB1</I> and <I>ABCC2</I>) may be candidate markers for predicting maculopapular eruption (MPE) induced by antituberculosis therapy. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in the <I>ABCB1</I> and <I>ABCC2</I> genes between 62 antituberculosis drug (ATD)-induced MPE cases and 159 ATD-tolerant controls using multivariate logistic regression analysis. There was no significant association between genetic polymorphisms in <I>ABCB1</I> and ATD-induced MPE (<I>P</I>>0.05). Among seven selected SNPs of <I>ABCC2</I>, IVS3-49C>T in intron and I1324I were associated with ATD-induced MPE (<I>P</I>=0.029 and 0.036, respectively). In an analysis of the <I>ABCC2</I> haplotypes (ht; -1549G>A_-24C>T_IVS3-49C>T_V417I), ht1[G-C-C-G] was significantly associated with ATD-induced MPE (<I>P</I>=0.032, OR=0.35, 95% CI: 0.16-0.95). No significant association between the other haplotypes and ATD-induced MPE was observed. An <I>ABCC2</I> haplotype is associated with the presence of ATD-induced MPE in patients with tuberculosis and may be a genetic risk factor for the development of MPE induced by ATD.</P>

Dexamethasone Inhibits TRAIL- and Anti-cancer Drugs-induced Cell Death in A549 Cells through Inducing NF-kappaB-independent cIAP2 Expression

Youn Seup Kim,Jae Seuk Park,Young Koo Jee,Kye Young Lee 대한암학회 2004 Cancer Research and Treatment Vol.36 No.5

Purpose: We have examined that dexamethasone inhibits apoptotic cell death of A549 lung epithelial cells through TRAIL and anti-cancer drugs. The purpose of the study is to determine the roles of GR, cIAP and NF-KappaB in this mechanism. Materials and Methods: In the A549 lung epithelial cell line, TRAIL, taxol, doxorubicine & gemcitabine were used to investigate cell toxicity. Cells were pretreated 12 hours in advance with dexamethasone. RU486 was pretreated 30 minutes before dexamethasone. Crystal violet assay was used for cell toxicity tests. Apoptosis assay was performed by taking morphologic surveys with fluorescent microscopy after double staining with Hoechst 33342 & propium iodide. RT-PCR was used to investigate the gene expression of cIAP1 & cIAP2 by dexamethasone. Ad-IKappaBalpha-SR transduction study was used for the role of NF-KappaB. Results: TRAIL and anti-cancer drug-induced apoptosis was partially suppressed in A549 cells pretreated with dexamethasone. The inhibitory effect on cell death disappeared in A549 cells pretreated with RU486. Using RT-PCR, changes of cIAP1 and cIAP2 genes manifestation in A549 cells subsequent to pretreatment with dexamethasone were examined. The results showed an increase in cIAP2 expression during a course of time which was suppressed by RU486 pretreatment. Induction of cIAP2 expression changes by dexamethasone was uniquely observed despite the blockade of NF-KappaB by Ad-Ikappa Balpha-SR transduction. Conclusions: These results suggest that dexamethasone inhibits TRAIL- and anti-cancer drug-induced apoptosis in A549 cells by inducing cIAP2 gene expression through a GR-mediated, NF-KappaB-independent pathway.(Cancer Res Treat. 2004;36:330-337)

천식 환자에서 재조합 Fibroblast growth factor 2의 안정성과 효능에 관한 전임상 연구

김윤섭 ( Youn Seup Kim ),장용호 ( Yong Ho Jang ),전지현 ( Ji Hyun Jeon ),서지희 ( Ji Hee Seo ),강수형 ( Soo Hyung Kang ),지영구 ( Young Koo Jee ) 대한천식알레르기학회 2014 Allergy Asthma & Respiratory Disease Vol.2 No.4

천식 환자에서 재조합 Fibroblast growth factor 2의 안정성과 효능에 관한 전임상 연구

김윤섭 ( Youn Seup Kim ),장용호 ( Yong Ho Jang ),전지현 ( Ji Hyun Jeon ),서지희 ( Ji Hee Seo ),강수형 ( Soo Hyung Kang ),지영구 ( Young Koo Jee ) 대한천식알레르기학회 2014 Allergy Asthma & Respiratory Disease Vol.2 No.3

Purpose: Fibroblast growth factor 2 (FGF2) has been shown to inhibit airway inflammation, mucus production, and airway hyperresponsiveness in mouse model of asthma. The aim of this study was to evaluate the safety and efficacy of inhaled recombinant FGF2 in asthmatic patients. Methods: Eight asthmatics were eligible for the study. All patients were admitted to a hospital, and recombinant FGF2 was administered using a nebulizer at a concentration of 4.5 ng/mL three times a day for one week. Pulmonary function test, methacholine bronchial provocation test, induced sputum analysis, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were performed at the beginning of wash-out period, before and after the treatment, and at the end of study. And all these parameters were compared before and after FGF2 treatment. Results: There were no serious adverse events associated with recombinant FGF2 during five-week study period. Daytime and nocturnal symptoms improved after the treatment (P=0.028 and P=0.012, respectively). AQLQ and ACT also improved after the treatment (P=0.017 and P=0.011, respectively). However, lung function, airway hyperresponsiveness, and airway inflammation showed no significant difference before and after the treatment. Conclusion: Inhaled recombinant FGF2 was safely used to eight asthmatics without any serious adverse events, and improved daytime and nocturnal symptoms, and quality of life in adult asthmatics. FGF2 may be a potential drug in the treatment of asthma.

Impulse Oscillometry(IOS)를 이용한 흡연자에서의 조기 기도폐쇄의 연구

김윤섭 ( Youn Seup Kim ),권숙희 ( Suk Hoe Kweon ),송미영 ( Mi Young Song ),유선미 ( Sun Mi Yoo ),박재석 ( Jae Seuk Park ),지영구 ( Young Koo Jee ),이계영 ( Kye Young Lee ),김건열 ( Keun Youl Kim ) 대한결핵 및 호흡기학회 1997 Tuberculosis and Respiratory Diseases Vol.44 No.5

천식 환자에서 재조합 Fibroblast growth factor 2의 안정성과 효능에 관한 전임상 연구

김윤섭 ( Youn Seup Kim ),장용호 ( Yong Ho Jang ),전지현 ( Ji Hyun Jeon ),서지희 ( Ji Hee Seo ),강수형 ( Soo Hyung Kang ),지영구 ( Young Koo Jee ) 대한소아알레르기호흡기학회 1992 소아알레르기 및 호흡기학회지 Vol.2 No.3

Purpose: Fibroblast growth factor 2 (FGF2) has been shown to inhibit airway inflammation, mucus production, and airway hyperresponsiveness in mouse model of asthma. The aim of this study was to evaluate the safety and efficacy of inhaled recombinant FGF2 in asthmatic patients. Methods: Eight asthmatics were eligible for the study. All patients were admitted to a hospital, and recombinant FGF2 was administered using a nebulizer at a concentration of 4.5 ng/mL three times a day for one week. Pulmonary function test, methacholine bronchial provocation test, induced sputum analysis, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were performed at the beginning of wash-out period, before and after the treatment, and at the end of study. And all these parameters were compared before and after FGF2 treatment. Results: There were no serious adverse events associated with recombinant FGF2 during five-week study period. Daytime and nocturnal symptoms improved after the treatment (P=0.028 and P=0.012, respectively). AQLQ and ACT also improved after the treatment (P=0.017 and P=0.011, respectively). However, lung function, airway hyperresponsiveness, and airway inflammation showed no significant difference before and after the treatment. Conclusion: Inhaled recombinant FGF2 was safely used to eight asthmatics without any serious adverse events, and improved daytime and nocturnal symptoms, and quality of life in adult asthmatics. FGF2 may be a potential drug in the treatment of asthma. (Allergy Asthma Respir Dis 2014;2:200-207)

진단이 내려지지 않은 만성기침 환자에서 양자펌프억제제의 치료효과

양주연 ( Joo Youn Yang ),이호연 ( Ho Youn Lee ),김남희 ( Nam Hee Kim ),김윤섭 ( Youn Seup Kim ) 대한결핵 및 호흡기학회 2006 Tuberculosis and Respiratory Diseases Vol.61 No.2

연구배경: 8주 이상 지속되는 만성 기침의 원인 중 하나인 위식도역류질환는 환자의 약 75%가 증상이 없으며, 진단을 위한 24시간 식도 pH감시가 침습적이고 검사가 어려워 진단 및 치료에 어려움이 있다. 따라서 만성 기침환자 중 후비루증후군 및 기관지 천식이 아닌 환자를 대상으로 양자펌프억제제를 투여하고 치료효과를 관찰하였다. 방법 및 대상: 기침증상이 8주 이상인 만성기침 환자 중 X-ray 소견상 이상이 없고 메타콜린 기관지유발시험상 음성이며, 후비루증후군 치료에 반응이 없었던 40명을 대상으로 하였다. 8주 이상 양자펌프억제제를 투여하였으며 50%이상 기침이 감소한 경우를 부분 반응군, 기침이 거의 소실된 경우를 완전 반응군으로 분류하였다. 결과: 대상자 40명중 29명만이 4주 이상 추적되었으며 이중 26명만이 8주까지 추적 관찰되었다. 29명중 남자가 9명, 여자가 20명이었으며 평균나이는 51세였다. 대상자들에서 기침 이외의 증상은 객담이 12%, 콧물이나 비폐색 등의 코 증상이 있는 환자는 10%, 속쓰림, 소화불량 등의 소화기 증상을 호소하는 환자는 13.4%였다. 29명중 4주간 투여 후 증상의 호전이 없는 환자가 3명(10.3%), 50% 이상의 증상호전을 보이는 환자가 22명(75.9%), 그리고 증상이 거의 소실된 환자가 4명(13.8%)로 약 90%정도의 환자가 기침의 증상호전이 있었다. 8주 투여 후 호전이 없는 환자가 2명(7.4%), 50% 이상 증상호전이 있는 환자가 8명(29.6%), 증상이 거의 소실된 환자가 16명(63.0%)이었다. 결론: 8주이상의 만성기침 환자에서 8주 이상 양자펌프억제제 투여 후 92.6%환자가 증상호전이 있었으며 이중 63%는 거의 소실되었다. 하지만 본 연구는 위약을 통한 대조군이 없는 관계로 그 결과의 해석에 어려움이 있다. 앞으로 좀더 많은 환자를 대상으로 하는 이중맹검시험이 필요할 것으로 생각된다. Background: Recent studies have suggested an association between chronic cough and gastroesophageal reflux. Our study aimed to assess the utility of a proton-pump inhibitor in unexplained chronic cough patients. Methods: Patients with chronic cough of unknown etiology were evaluated using a chest x-ray, methacholine challenge test, and an empirical trial of postnasal drip therapy. After excluding other potential causes of the cough, forty patients were included in the study and treated for 8 weeks with a proton-pump inhibitor. Results: Eleven and three patients in the first and second 4 weeks were lost to follow-up, leaving twenty-six patients finally included in the study. Of these patients, two were unimproved, eight partially responded to the proton-pump inhibitor and sixteen responded completely after the 8 week treatment. Conclusion: We suggest that empirical treatment with a proton pump inhibitor in all patients with persistent cough, which is not secondary to asthma or postnasal drip syndrome, represents a practical and simple approach to this ailment. (Tuberc Respir Dis 2006; 60: 137-142)

Poster Session : PS 1621 ; Miscellaneous : Genetic Polymorphisms in Superoxide Dismutase Genes (SOD1, SOD2 and SOD3) and Maculopapular Eruption Induced by Antituberculosis Drugs

( Sang Heon Kim ),( Sang Hoon Kim ),( Jang Won Sohn ),( Ho Joo Yoon ),( Dong Ho Shin ),( Sung Soo Park ),( Jae Hyung Lee ),( Byoung Hoon Lee ),( Youn Seup Kim ),( Jae Seuk Park ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Maculopapular eruption is the most common adverse reactions to antituberculosis drugs (ATD), often leading to discontinuation of the medication. While the mechanisms of ATD-induced MPE are not well understood, oxidative stress induced by the ATD metabolites could play a role in drug-induced MPE. We aimed to examine if the genetic polymorphisms in superoxide dismutase genes (SOD1, SOD2 and SOD3) were associated with MPE induced by ATD. Methods: We enrolled 75 patients with ATD-induced MPE and 237 ATD-tolerant control by regular monitoring of adverse reactions to ATD. Genotyping was performed 4 single nucleotide polymorphisms (SNP) in SOD1 (rs2070424), SOD2 (rs4880) and SOD3 (rs2536512 and rs1799895) in patients with ATD-induced MPE and patients tolerant to ATD. Genotype-phenotype association was examined by logistic regression analysis adjusting for gender and age. Results: In SOD1, there was signifi cant association between rs2070424 (Ivs3-251A/G) and ATD-induced MPE (P = 0.019, OR = 2.42, 95% CI 1.16-5.05), with higher frequency of genotype, GA + GG, in patients with ATD-induced MPE compared with ATD-tolerant controls. The other polymorphisms in SOD2 and SOD3 did not show signifi cant difference of genotypes between case and control group. Conclusions: Intron SNP rs2070424 of SOD1 (Ivs3-251A/G) showed signifi cant association with ATD-induced MPE. These fi ndings suggest that this genetic variant may increase the risk of ATD-induced MPE.

Free Paper Presentation : OS-72 ; A Randomized Phase III Study of Docetaxel Plus Cisplatin Versus Pemetrexed Plus Cisplatin in First Line Non-Squamous Non-Small Cell Lung Cancer (NSq-NSCLC)

( Young Chul Kim ),( In Jae Oh ),( Kyu Sik Kim ),( Tae Won Jang ),( Yoo Duk Choi ),( Youn Seup Kim ),( Kwan Ho Lee ),( Kyung Chul Shin ),( Chi Young Jung ),( Sei Hoon Yang ),( Seung Hun Jang ),( Jeong 대한결핵 및 호흡기학회 2014 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.118 No.-

Background: For patients with NSq-NSCLC, pemetrexed(A) plus cisplatin(P) was superior to gemcitabine(G) plus cisplatin(P) in terms of efficacy and toxicity. However, there have been no prospective phase III trial directly comparing the efficacy of AP with docetaxel+cisplatin (DP) in NSq-NSCLC. Methods: We undertook an open-label phase III trial with recruitment between August 2011, and December 2013, at 14 centers in Korea. Patients with chemotherapy-naive NSq-NSCLC were randomized into 3 weekly cisplatin 70 mg/m2 with either docetaxel 60mg/m2 (DP) or pemetrexed 500mg/m2 (AP) for up to 4 cycles with stratification strata of performance status and sex. The primary objective was to assess PFS and the secondary endpoints were response rate, overall survival (OS) and safety. Treatment response was evaluated according to RECIST version 1.1. Results: After 149 patients were randomized into AP (n=77) and DP (n=72) arm, study team finished enrollment because of approval and popular use of maintenance pemetrexed treatment in Korea. Clinical characteristics including sex, age, and performance status were well balanced between the arms. Number of cycles and relative dose intensity were not significantly different between the arms. Partial remission was observed in 24 (31.2%) and 24 (33.3%) cases of AP and DP group, respectively. Median PFS was 4.7 months (95% confidence interval, CI 4.4~5.1) in AP arm and 4.6 months (3.7~5.6) in DP arm. Rate of grade 3 or 4 neutropenia and febrile neutropenia, number of serious adverse events were significantly higher in DP compared to AP arm. Conclusions: Although both regimen showed similar PFS and response rate, more frequent adverse events and higher toxicities were observed in DP arm. (ClinicalTrials.gov Identifier: NCT01282151)