Adenosine Mitigates Low-Dose Zidovudine-Induced Rat Liver Damage by Modulating Redox State and Pro-Inflammatory Cytokine Production

Author(s): Martha Lucinda Contreras-Zentella, Armando Butanda-Ochoa, Lourdes Sánchez-Sevilla, Rodolfo Paredes-Díaz, and Rolando Hernández-Muñoz

Zidovudine (AZT) has significantly reduced mortality and morbidity among AIDS patients, but has also been linked to adverse events, including hepatotoxicity, which leads to liver steatosis. In contrast, adenosine (ADO) has shown effectiveness as a hepatoprotective agent against both acute and chronic liver damage. This study aimed to examine the adverse effects of chronic low-dose AZT administration and potential mitigation of these effects through co-administration with ADO in rats. We evaluated tissue inflammation and the liver redox state during the development of AZT-induced fatty liver. Wistar rats treated with AZT and adenosine were assessed for various parameters, including serum enzyme markers, histological changes, and serum levels of insulin, glucagon, pro-inflammatory cytokines, and redox state markers. Chronic oral AZT administration resulted in elevated serum liver enzyme activity and slight liver steatosis characterized by micro-vesicular fat distribution. These effects were accompanied by reduced insulin and glucagon levels, increased serum pro-inflammatory cytokine levels, and disruptions of cellular redox states. The co-administration of ADO reduced the harmful effects of AZT, reduced the production of most inflammatory molecules, increased serum insulin and glucagon levels, and restored the liver cellular redox state. In conclusion, our findings indicate a connection between blood insulin and glucagon levels and cellular redox state, altered by chronic low-dose AZT administration, which is likely linked to mitochondrial integrity and metabolism. Notably, these effects were partially alleviated by co-administration of ADO.