Youn-Seup Kim

Design and construction of the KSTAR tokamak

The extensive design effort for KSTAR has been focused on two major aspects of the KSTAR project mission - steady-state-operation capability and advanced tokamak physics. The steady state aspect of the mission is reflected in the choice of superconducting magnets, provision of actively cooled in-vessel components, and long pulse current drive and heating systems. The advanced tokamak aspect of the mission is incorporated in the design features associated with flexible plasma shaping, double null divertor and passive stabilizers, internal control coils and a comprehensive set of diagnostics. Substantial progress in engineering has been made on superconducting magnets, the vacuum vessel, plasma facing components and power supplies. The new KSTAR experimental facility with cryogenic system and deionized water cooling and main power systems has been designed, and the construction work is under way for completion in 2004.

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

AIMSnAlthough 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.nnnMATERIALS & METHODSnWe 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.nnnRESULTSnAmong 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.nnnCONCLUSIONnThese 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.

GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans.

Adverse reactions induced by antituberculosis drugs (ATD) often result in serious morbidities, impeding scheduled treatment and cure. In the development of ATD-induced adverse reactions, glutathione S-transferase has been suggested to play a protective role as an intracellular scavenger by conjugating toxic reactive metabolites of ATD. This study examined the association of null mutations in GST enzyme genes (GSTT1 and GSTM1) with the development of ATD-induced hepatitis and cutaneous reactions. We compared the frequencies of GSTT1 and GSTM1 null mutations in 57 patients with hepatitis, 94 patients with cutaneous adverse reactions, and 190 ATD-tolerant controls. The frequency of null mutations in GSTT1 and GSTM1 in patients with ATD-induced hepatitis was not significantly different from that of controls (59.6% vs. 54.2% and 45.6% vs. 54.7%, respectively). Additionally, no significant difference was observed in the frequency of either null mutation in patients with ATD-induced cutaneous reactions, including maculopapular eruption, compared with controls (58.5% vs. 54.1% for GSTT1 and 59.6% vs. 54.6% for GSTM1). These findings indicate that GSTT1 and GSTM1 null mutations are not associated with the development of ATD-induced hepatitis or cutaneous reactions in this Korean population, and suggest that glutathione S-transferase enzymes do not play important roles in the pathogenesis of these conditions.

TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis.

While the mechanisms underlying the development of drug‐induced liver injury are not clear, there is evidence to suggest that tumor necrosis factor‐α (TNF‐α) plays an important role in drug‐ or drug metabolite‐induced immune responses. We hypothesized that polymorphisms in the TNF‐α gene are associated with anti‐tuberculosis drug (ATD)‐induced hepatitis.

Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs

Unusual drug accumulation is a common mechanism underlying serious drug-induced liver injury. Polymorphisms in three drug transporter genes (ABCB1, SLCO1B1 and ABCC2) may be risk markers for hepatitis induced by the unusual accumulation of anti-tuberculosis drugs (ATDs). We therefore investigated whether polymorphisms and haplotypes of these genes are associated with ATD-induced hepatitis by comparing the frequencies and distributions of single nucleotide polymorphisms and haplotypes of these three drug transporter genes among 67 patients with ATD-induced hepatitis and 159 patients tolerant to ATDs using a multivariate logistic regression analysis. We found that the frequencies of polymorphisms and haplotypes of ABCB1, SLCO1B1 and ABCC2 were similar in patients with ATD-induced hepatitis and ATD-tolerant controls. The present results suggest that these drug transporters do not play important roles in the pathogenesis of ATD-induced hepatitis in Korean patients.

NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption

PurposeIt has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE.MethodsWe enrolled 62 patients with ATD-induced MPE (mean age 47.2u2009±u200919.0, male 59.7%) and 159 patients without any adverse reactions to ATD (mean age 42.8u2009±u200917.6, male 65.4%), among patients with pulmonary tuberculosis (TB) and/or TB pleuritis and treated with first-line anti-TB medications, including isoniazid, rifampin, ethambutol, and pyrazinamide. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in four drug-metabolizing enzymes (N-acetyltransferase 2 (NAT2), cytochrome P450 (CYP) 2xa0C9, CYP2C19, and CYP2E1) among patients with ATD-induced MPE and patients tolerant to ATD using a multivariate logistic regression analysis. These analyses were made without identification of the responsible ATD.Results−1565xa0Cu2009>u2009T of CYP2C9 showed a significant association with ATD-induced MPE (Pu2009=u20090.022, ORu2009=u20090.23, 95% CI 0.07–0.78), with a lower frequency of genotypes carrying minor alleles (CT or TT) in the case group than in the controls. Additionally, W212X of CYP2C19 was significantly associated with the risk of ATD-induced MPE (Pu2009=u20090.042, ORu2009=u20090.27, 95% CI 0.09–0.82). In an analysis of the CYP2C19–CYP2C9 haplotypes (−1418xa0Cu2009>u2009T_W212X_−1565xa0Cu2009>u2009T_−1188xa0Cu2009>u2009T), ht3[T-A-T-C] showed a significant association with the development of ATD-induced MPE (Pu2009=u20090.012, ORu2009=u20090.13, 95% CI 0.03–0.57). No significant associations between the other genetic polymorphisms and ATD-induced MPE were observed.ConclusionsCYP2C19 and CYP2C9 genetic polymorphisms are significantly associated with the risk of developing ATD-induced MPE, and the genetic variants in NAT2 and CYP2E1 are not closely related to the development of this adverse reaction.

Associations of GCLM, gclc and GSTP1 gene polymorphisms and antituberculosis drugs-induced hepatitis

Background Antituberculosis drugs (ATD) is the most common cause of drug-induce liver injury in many countries. While the mechanism of ATD-induced hepatitis is poorly understood, oxidative stress is suggested to be involved in the development of liver injury to drug metabolites. In this regards, we explored the possible associations between glutathione related enzymes (GCLM, GCLC and GSTP1) gene polymorphisms and ATD-induced hepatitis.