한빛사논문
- 조회257
Jihoon G. Yoon 1,2,11, Dong Geon Jang 1,11, Sung-Gyu Cho 3,11, Chaeyoung Lee 1, Shin Hye Noh 1,4, Soo Kyung Seo 1, Jung Woo Yu 1, Hyeon Woo Chung 3, KyeoRe Han 3, Soon Sung Kwon 1,5, Dai Hoon Han 6, Jaeseong Oh 7, In-Jin Jang 7, Sang-Hoon Kim 8, Young-Koo Jee 9, Hyun Lee 10, Dong Won Park 10, Jang Won Sohn 10, Ho Joo Yoon 10, Chul Hoon Kim 1, Jae Myun Lee 3,12,*, Sang-Heon Kim 10,12,* and Min Goo Lee 1,4,12,*
1Department of Pharmacology, BK21 Project of Yonsei Advanced Medical Science, Woo Choo Lee Institute for Precision Drug Development, Yonsei University College of Medicine, Seoul, Republic of Korea.
2Department of Genomic Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
3Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
6Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
7Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
8Department of Internal Medicine, Eulji University School of Medicine, Seoul, Republic of Korea.
9Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Republic of Korea.
10Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea.
11These authors contributed equally: Jihoon G. Yoon, Dong Geon Jang, Sung-Gyu Cho.
12These authors jointly supervised this work: Jae Myun Lee, Sang-Heon Kim, Min Goo Lee.
*Corresponding authors: correspondence to Jae Myun Lee, Sang-Heon Kim or Min Goo Lee
Abstract
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. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-04)
- 국내 연구진
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