Molecular Initiating Events Associated with Drug-Induced Liver Malignant Tumors: An Integrated Study of the FDA Adverse Event Reporting System and Toxicity Predictions.

Kota Kurosaki,Yoshihiro Uesawa

doi:10.3390/biom11070944

Abstract

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure–activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.

Highlights

Based on the hypothesis that drug-induced liver malignant tumors (LMTs) are triggered by nuclear receptors (NR) and stress response pathways (SRs) modulation of potential endocrine-disrupting chemicals (EDCs), we used the quantitative structure–activity relationship platform for toxicity prediction to identify potential molecular initiating events (MIEs) that are specific to LMT-inducing drug classes
56 NRs and SRs, using Toxicity Predictor [19], which is a QSAR prediction platform for chemical toxicity, and, using these activities, we identified potential MIEs that are specific to the class of signal-detected LMT-inducing drugs
Our results showed that estrogen-related receptor (ERR) antagonist activity is a potential MIE for drug-induced LMTs

Summary

Introduction

Drug-induced liver injury (DILI) is the most common adverse drug event (ADE). Causing medicinal product withdrawal or major regulatory action [1]. More than 1100 products used by humans on a relatively frequent basis, such as medicines, herbal and other natural products, minerals, and “recreational” or illicit chemical substances, have been identified as potential liver injury-inducing substances [2]. As described by Katarey et al, liver malignant tumors (LMTs) represent a serious adverse event associated with DILI [3]. DILI-induced hepatocellular death leads to clinical manifestations of hepatitis and can induce hepatic malignancies if DILI progresses. Due to the regulatory implications and potential for substantial impacts of drug-induced LMT on patients’ lives, early detection of LMT-inducing drugs and developing an understanding of the compound’s biological interactions are important considerations across all phases of pharmaceutical development

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