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논문 기본 정보

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학술저널
저자정보
Yoon Jihoon G. (Yonsei University College of Medicine) Jang Dong Geon (Yonsei University College of Medicine) Cho Sung-Gyu (Yonsei University College of Medicine) Lee Chaeyoung (Yonsei University College of Medicine) Noh Shin Hye (Yonsei University College of Medicine) Seo Soo Kyung (Yonsei University College of Medicine) Yu Jung Woo (Yonsei University College of Medicine) Chung Hyeon Woo (Yonsei University College of Medicine) Han KyeoRe (Yonsei University College of Medicine) Kwon Soon Sung (Yonsei University College of Medicine) Han Dai Hoon (Yonsei University College of Medicine) Oh Jaeseong (Seoul National University College of Medicine and Hospital) Jang In-Jin (Seoul National University College of Medicine and Hospital) Kim Sang-Hoon (Eulji University School of Medicine) Jee Young-Koo (Dankook University College of Medicine) Lee Hyun (Hanyang University College of Medicine, Seoul) Park Dong Won (Hanyang University College of Medicine) Sohn Jang Won (Hanyang University College of Medicine) Yoon Ho Joo (Hanyang University College of Medicine) Kim Chul Hoon (Yonsei University College of Medicine) Lee Jae Myun (Yonsei University College of Medicine) Kim Sang-Heon (Hanyang University College of Medicine, Seoul) Lee Min Goo (Yonsei University College of Medicine)
저널정보
대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine Vol.56
발행연도
2024.3
수록면
1 - 13 (13page)
DOI
10.1038/s12276-024-01172-8

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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.

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