http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity
Yoon Jihoon G.,Jang Dong Geon,Cho Sung-Gyu,Lee Chaeyoung,Noh Shin Hye,Seo Soo Kyung,Yu Jung Woo,Chung Hyeon Woo,Han KyeoRe,Kwon Soon Sung,Han Dai Hoon,Oh Jaeseong,Jang In-Jin,Kim Sang-Hoon,Jee Young-K 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-
Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5–13.2], P = 7.2 × 10−6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5–1423], P = 7.5 × 10−6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility.
First Cases of Spinocerebellar Ataxia 42 in Two Korean Families
손효신,Jihoon G. Yoon,Man Jin Kim,문장섭,김한준 대한파킨슨병및이상운동질환학회 2023 Journal Of Movement Disorders Vol.16 No.1
we identified the first Korean cases of SCA42 in two unrelated families. This report highlights the importance of NGS testing in Korean patients with ataxia who remain undiagnosed after testing for tandem repeat disorders. As the prevalence of SCA42 in each ethnicity or country is unknown, further studies are warranted to unravel the genetic characteristics of this disease.
( Myung-a Cho ),( Jihoon G Yoon ),( Vitchan Kim ),( Harim Kim ),( Rowoon Lee ),( Min Goo Lee ),( Donghak Kim ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.6
Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants―including three novel variants F69S, L310V, and Q324X―that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high k<sub>cat</sub> values; however, their K<sub>m</sub> values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher K<sub>m</sub> and lower k<sub>cat</sub> values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower k<sub>cat</sub> and K<sub>m</sub> values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.