Genotoxic Drug‐Induced Hepatotoxicity: An In Silico Prediction Using <i>Rattus norvegicus</i> Microarray Gene Expression Data

Most genotoxic compounds are potentially used for therapeutic purposes against various diseases, particularly cancer types, either alone or in combination with other drugs. However, these drug combinations have detrimental adverse effects during or post the treatment procedures. To deeply understand the molecular mechanisms underlying the onset or progression of toxicity upon drug treatment, the current work establishes a systematic in silico approach that applies the microarray gene expression data to predict specific mechanisms through which hepatotoxicity is induced. To achieve this, about six in vivo genotoxic drugs are selected such as three chemotherapeutic drugs (cyclophosphamide [CP], cisplatin [CPT], and etoposide [ETP]) and three antibiotic drugs (ethionamide [ETO], chloramphenicol [CPL], and erythromycin ethyl succinate [EES]) based on their direct or indirect mechanisms in inducing hepatotoxicity. Rattus norvegicus liver tissue microarray expression datasets for the selected genotoxic drugs that are available in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation Systems (Open TG-GATES) database have been unpacked using robust software such as dChip and R to identify the differentially expressed genes (DEGs). Further, protein-protein interaction (PPI) networks are constructed, and the genotoxic drugs are functionally analyzed for Gene Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) using the STRING v12 database. The study has been extended to principal component analysis (PCA) wherein the genotoxic drugs are combined to examine the effects of combinations against hepatotoxicity. The study concludes that 4 of the 15 combinations-CPT/CPL, CP/CPT, EES/CP, and ETP/CPL-possess the potency in causing hepatotoxicity, possibly through chemical carcinogenesis and reactive oxygen species (ROS) receptor activation mechanism leading to genotoxic drug-induced liver injury.