Mechanisms of Drug-Induced Liver Injury: Pharmacological Insights and Biomarker-Based Detection Approaches

Abstract: Drug-induced liver injury (DILI) is one of the most significant and chronic problems in the clinical pharmacology and toxicology, and a primary cause of acute hepatic failure, developmental drug attrition, and post-marketing regulatory events. Diversified pharmacological, metabolic, and immunological pathways are the factors which made DILI to be complex and heterogeneous and, therefore, difficult to predict, identify early and address clinically. The purpose of the review was to elucidate the mechanistic basis of DILI in a comprehensive way and mention the significance of biomarker-based strategies in terms of better detection and risk assessment. Experimental and clinical studies have recently shown that DILI is a product of interconnected pathways in which reactive metabolite formation, oxidative stress, mitochondrial dysfunction, bile acid transport disruption, and innate and adaptive immune activation occur. The recent developments in pharmacogenomics have also discovered that genetic diversity in drug-metabolizing enzymes, transporters, and immune regulating systems play a big role in determining an individual susceptibility to liver damage. More recent studies have also highlighted the shortcomings of traditional liver enzymes as a diagnostic method and it has led to the emergence of new biomarkers which can more reliably indicate the causative pathways of hepatocellular injury and inflammation. Newer biosensors like circulating microRNAs, cytokeratin-18 fragments, high-mobility group box-1 protein and bile acid signatures have demonstrated better sensitivity and specificity in early DILI diagnosis, phenotypic grouping and prognostic assessments. Combining the mechanistic pharmacological knowledge with biomarker discovery adds to the knowledge of the DILI pathogenesis and provides more reliable safety assessment during the drug life cycle. Conclusively, DILI can be viewed as a multifactorial and mechanism-based adverse response that must be addressed through a translational process that is between molecular toxicology and practical clinical use. The utilization of mechanism-based biomarkers, in addition to traditional methods has a huge potential to enhance the accuracy of diagnosis, reduce patient risk and enhance the development of safer and more effective drug development approaches.