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Mitochondrial DNA Variants in Patients with Liver Injury Due to Anti-Tuberculosis Drugs
- Source :
- Journal of Clinical Medicine, Vol 8, Iss 8, p 1207 (2019)
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid’s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. Results: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I’s NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Conclusions: Variants in complex I’s subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.
- Subjects :
- Drug-induced liver injury
tuberculosis
mitochondria
DNA variants
complex I
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 20770383
- Volume :
- 8
- Issue :
- 8
- Database :
- Directory of Open Access Journals
- Journal :
- Journal of Clinical Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.5e43b02d0e594a65a590dedd765117cb
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/jcm8081207