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Azithromycin induces liver injury in mice by targeting the AMPK/Nrf2 pathway
Qixiang Xu1, Cuifeng Zhang2,3, Jingwen Lu2,3
1School of Pharmacology, Wannan Medical College, Wuhu, China.
Background:
Azithromycin is an antibacterial and anti-inflammatory drug widely used for the treatment of various diseases, including those caused by atypical pathogens, bacterial or viral infections, chronic sinusitis, and bronchial asthma, particularly in pediatric patients. However, concerns have emerged regarding its hepatotoxicity and its precise mechanism of action remains unclear.
Objective:
To investigate the molecular mechanisms responsible for azithromycin-induced acute liver injury to advance our understanding of the progression and pathogenesis of antibiotic-induced liver damage, and to improve prevention and treatment strategies.
Materials And Methods:
C57BL/6 mice, Nrf2-/- mice, and primary hepatocytes were used. Primary hepatocytes from mice were isolated using a two-step perfusion method and cultured in vitro via the 'sandwich' culture model.
Results:
The exposure to azithromycin resulted in increased apoptosis and reactive oxygen species (ROS) levels. In mouse models, intraperitoneal administration of azithromycin at varying concentrations and time points substantially induced hepatic disarray, swelling, and dysfunction. Azithromycin markedly upregulated the mRNA and protein levels of phosphorylated adenosine-activated protein kinase (AMPK) while downregulating nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NADPH: quinone oxidoreductase 1 (NQO-1). Moreover, HO-1 and NQO-1 protein levels remained largely unaffected in primary hepatocytes co-cultured with azithromycin in Nrf2-/- mice.
Conclusions:
Our findings suggest that azithromycin-induced acute liver injury is mediated by suppression of Nrf2 activation and ROS production. This sheds light on the potential mechanisms involved in azithromycin-induced liver damage, underscoring the importance of exploring targeted interventions to mitigate the hepatotoxic effects.
Insights
Azithromycin causes liver injury by suppressing Nrf2 activation and increasing reactive oxygen species (ROS). This study clarifies mechanisms of antibiotic-induced liver damage, aiding prevention and treatment strategies.
Area of Science:
- Pharmacology
- Toxicology
- Hepatology
Background:
- Azithromycin, an antibiotic and anti-inflammatory drug, is widely used for various infections.
- Concerns exist regarding azithromycin's hepatotoxicity, with unclear underlying mechanisms.
- Understanding azithromycin-induced liver injury is crucial for patient safety.
Purpose of the Study:
- To elucidate the molecular mechanisms of azithromycin-induced acute liver injury.
- To advance the understanding of antibiotic-induced liver damage pathogenesis.
- To inform improved prevention and treatment strategies for drug-induced liver injury.
Main Methods:
- Utilized C57BL/6 mice, Nrf2 knockout mice, and primary hepatocytes.
- Employed a two-step perfusion method for hepatocyte isolation.
- Used an in vitro 'sandwich' culture model for hepatocyte studies.
Main Results:
- Azithromycin exposure increased apoptosis and reactive oxygen species (ROS) levels.
- In vivo, azithromycin induced hepatic disarray, swelling, and dysfunction.
- Azithromycin downregulated Nrf2, HO-1, and NQO-1, while upregulating p-AMPK; effects on HO-1/NQO-1 were absent in Nrf2-/- hepatocytes.
Conclusions:
- Azithromycin-induced acute liver injury is linked to Nrf2 pathway suppression and elevated ROS.
- Findings highlight the role of Nrf2 in mitigating azithromycin hepatotoxicity.
- Targeted interventions focusing on Nrf2 activation may prevent azithromycin-induced liver damage.
