Molecular Pharmacology of Ethanol-Induced Hepatotoxicity in Nigeria: Characterising Oxidative Stress, Mitochondrial Dysfunction, and CYP2E1-Mediated Mechanisms

Background: Alcohol-related liver disease is an emerging burden in Nigeria, where locally brewed spirits with high ethanol concentrations and toxic additives are widely consumed. Despite rising clinical relevance, the molecular pharmacological mechanisms of ethanol hepatotoxicity in the Nigerian context, including the role of CYP2E1 genetic polymorphisms prevalent in African populations, are not well characterised. This study provides a detailed molecular pharmacological investigation of ethanol-induced hepatotoxicity relevant to the Nigerian population. Methods: In vitro studies used primary human hepatocytes and HepG2 cells treated with concentrations of ethanol mirroring acute and chronic exposure paradigms. In vivo chronic ethanol exposure was modelled in Wistar rats receiving local alcohol preparations for 12 weeks. Mechanistic endpoints included CYP2E1 protein expression and activity, mitochondrial membrane potential (JC-1 staining), reactive oxygen species generation (DCFH-DA), mitophagy markers (Parkin, LC3-II), and NLRP3 inflammasome activation. CYP2E1 genotyping was performed in 80 Nigerian alcohol-dependent patients to characterise variant frequency. Results: Chronic ethanol significantly upregulated CYP2E1 expression and activity in vitro and in vivo. Mitochondrial membrane potential was significantly reduced alongside accumulation of mitophagy intermediates. NLRP3 inflammasome activation was confirmed in chronic exposure models. The CYP2E1 c2 allele, associated with reduced CYP2E1 activity, was found in 19 percent of Nigerian patients. Conclusion: Ethanol hepatotoxicity in the Nigerian context involves CYP2E1-mediated oxidative injury, mitochondrial dysfunction, and NLRP3 inflammasome-driven inflammation. Population CYP2E1 variant prevalence has implications for individual susceptibility profiling. Keywords: ethanol hepatotoxicity, CYP2E1, oxidative stress, mitochondrial dysfunction, alcohol-related liver disease