دورية أكاديمية
Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity.
| العنوان: | Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity. |
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| المؤلفون: | Yoon JG; Department 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.; Department of Genomic Medicine, Seoul National University Hospital, Seoul, Republic of Korea., Jang DG; Department 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., Cho SG; Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea., Lee C; Department 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., Noh SH; Department 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.; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea., Seo SK; Department 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., Yu JW; Department 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., Chung HW; Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea., Han K; Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea., Kwon SS; Department 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.; Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea., Han DH; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea., Oh J; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea., Jang IJ; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea., Kim SH; Department of Internal Medicine, Eulji University School of Medicine, Seoul, Republic of Korea., Jee YK; Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Republic of Korea., Lee H; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea., Park DW; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea., Sohn JW; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea., Yoon HJ; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea., Kim CH; Department 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., Lee JM; Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea. jaemyun@yuhs.ac., Kim SH; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea. sangheonkim@hanyang.ac.kr., Lee MG; Department 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. mlee@yuhs.ac.; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. mlee@yuhs.ac. |
| المصدر: | Experimental & molecular medicine [Exp Mol Med] 2024 Mar; Vol. 56 (3), pp. 570-582. Date of Electronic Publication: 2024 Mar 01. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9607880 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2092-6413 (Electronic) Linking ISSN: 12263613 NLM ISO Abbreviation: Exp Mol Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Jan. 2013- : New York : Nature Publishing Group Original Publication: Seoul : Korean Society of Medical Biochemistry and Molecular Biology, 1996- |
| مواضيع طبية MeSH: | Arylamine N-Acetyltransferase*/genetics , Arylamine N-Acetyltransferase*/metabolism , Tuberculosis*/drug therapy , Tuberculosis*/genetics , Chemical and Drug Induced Liver Injury*/genetics , Mitochondrial Diseases*, Humans ; Isoniazid/toxicity ; Copper/toxicity ; Copper/therapeutic use ; Antitubercular Agents/toxicity ; Genotype |
| مستخلص: | 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. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | HI15C1543 Korea Health Industry Development Institute (KHIDI); 2022R1A2C3002917 National Research Foundation of Korea (NRF); 2022R1A4A1031336 National Research Foundation of Korea (NRF) |
| المشرفين على المادة: | V83O1VOZ8L (Isoniazid) 789U1901C5 (Copper) EC 2.3.1.5 (Arylamine N-Acetyltransferase) 0 (Antitubercular Agents) EC 2.3.1.5 (NAT2 protein, human) |
| تواريخ الأحداث: | Date Created: 20240229 Date Completed: 20240403 Latest Revision: 20240404 |
| رمز التحديث: | 20240404 |
| مُعرف محوري في PubMed: | PMC10984958 |
| DOI: | 10.1038/s12276-024-01172-8 |
| PMID: | 38424191 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2092-6413 |
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| DOI: | 10.1038/s12276-024-01172-8 |