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.
Highlights
Hepatotoxicity is the most severe adverse effect of antituberculosis therapy [1]
No differences were discovered between patients with drug-induced liver injury (DILI) and those without regarding age, sex, body mass index, smoking history, coexisting diseases, and N-acetyltransferase 2 (NAT2) genotype distribution
The oxidative phosphorylation (OXPHOS) system consists of a series of enzymes, including complex I (NADH: ubiquinone oxidoreductase), II, III, IV and V (ATP synthase), all located in the inner membrane of mitochondria, and this system completes the final part of energy generation
Summary
Hepatotoxicity is the most severe adverse effect of antituberculosis (anti-TB) therapy [1]. Mitochondrial dysfunction, especially those involving complex I, the largest enzyme catalyzing OXOPHOS system, may be involved in DILI by anti-TB drugs This remains, debatable since a recent in-vivo study using mouse model reveals contradictory findings, showing that cotreatment with rotenone and INH did not result in histological evidence of liver injury in wild-type mice and mice with impaired immune tolerance [12]. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. 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
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