bedaquiline and Chemical-and-Drug-Induced-Liver-Injury

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Diarylquinolines; Humans; Long QT Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bedaquiline was approved by USFDA in 2012 for pulmonary MDR-TB. The IC

Topics: Antitubercular Agents; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Diarylquinolines; Drug Development; Humans; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

Bedaquiline (BDQ) is a new class of anti-tubercular (anti-TB) drugs and is currently reserved for multiple drug resistance (MDR-TB). However, after receiving fast-track approval, its clinical studies demonstrate that its treatment is associated with hepatotoxicity and labeled as 'boxed warning' by the USFDA. No data is available on BDQ to understand the mechanism for drug-induced liver injury (DILI), a severe concern for therapeutic failure/unbearable tolerated toxicities leading to drug resistance. Therefore, we performed mechanistic studies to decipher the potential of BDQ at three dose levels (80 to 320 mg/kg) upon the repeated dose administration orally using a widely used mice model for TB. Results of BDQ treatment at the highest dose level showed that substantial increase of hepatic marker enzymes (SGPT and SGOT) in serum, oxidative stress marker levels (MDA and GSH) in hepatic tissue, and pro-inflammatory cytokine levels (TNF-α, IL-6, and IL-1β) in serum compared to control animals. Induction of liver injury situation was further evaluated by Western blotting for various protein expressions linked to oxidative stress (SOD, Nrf2, and Keap1), inflammation (NF-ĸB and IKKβ), apoptosis (BAX, Bcl-2, and Caspase-3) and drug metabolism enzymes (CYP3A4 and CYP2E1). The elevated plasma level of BDQ and its metabolite (N-desmethyl BDQ) were observed, corresponding to BDQ doses. Histopathological examination and SEM analysis of the liver tissue corroborate the above-mentioned findings. Overall results suggest that BDQ treatment-associated generation of its cytotoxic metabolite could act on CYP2E1/NF-kB pathway to aggravate the condition of oxidative stress, inflammation, and apoptosis in the liver and precipitating hepatotoxicity.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Inflammation; Kelch-Like ECH-Associated Protein 1; Liver; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress