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Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.

ABSTRACT: PURPOSE:Autosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V2 receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury. METHODS:In prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathematical model of drug-induced liver injury. In the current study, we evaluated lixivaptan, another proposed ADPKD treatment and vasopressin V2 receptor antagonist, using DILIsym®. Simulations were conducted that assessed the potential for lixivaptan and its three main metabolites to cause hepatotoxicity due to three injury mechanisms: bile acid accumulation, mitochondrial dysfunction, and oxidative stress generation. Results of these simulations were compared to previously published DILIsym results for tolvaptan. RESULTS:No ALT elevations were predicted to occur at the proposed clinical dose for lixivaptan, in contrast to previously published simulation results for tolvaptan. As such, lixivaptan was predicted to have a markedly lower risk of hepatotoxicity compared to tolvaptan with respect to the hepatotoxicity mechanisms represented in DILIsym. CONCLUSIONS:These results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity.

SUBMITTER: Woodhead JL

PROVIDER: S-EPMC6944674 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.

Woodhead J L JL Pellegrini L L Shoda L K M LKM Howell B A BA

Pharmaceutical research 20200106 2

<h4>Purpose</h4>Autosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V<sub>2</sub> receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury.<h4>Methods</h4>In prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathemat ...[more]

PMID: 31909447

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Project description:BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD), a common of monogenetic disorder caused by the polycystic kidney disease-1 (PKD1) or PKD2 genes deficiency. In this study, we have re-analyzed a microarray dataset to generate a holistic view of this disease. METHODOLOGY:GSE7869, an expression profiling dataset was downloaded from the Gene Expression Omnibus (GEO) database. After quality control assessment, using GEO2R tool of GEO, genes with adjusted p-value???0.05 were determined as differentially expressed (DE). The expression profiles from ADPKD samples in different sizes were compared. Using CluePedia plugin of Cytoscape software, the protein-protein interaction (PPI) networks were constructed and analyzed by Cytoscape NetworkAnalyzer tool and MCODE application. Pathway enrichment analysis of clustered genes by MCODE with the high centrality parameters in PPI networks was performed using Cytoscape ClueGO plugin. Moreover, by Enrichr database, microRNAs (miRNAs) and transcription factors (TFs) targeted DE genes were identified. RESULTS:In this study to explore the molecular pathogenesis of kidney in ADPKD, mRNA expression profiles of cysts from patients in different sizes were re-analyzed. The comparisons were performed between normal with minimally cystic tissue (MCT) samples, MCTs with small cysts, and small cysts with large cysts. 512, 7024, and 655 DE genes were determined, respectively. The top central genes, e.g. END1, EGFR, and FOXO1 were identified with topology and clustering analysis. DE genes that were significantly enriched in PPI networks are critical genes and their roles in ADPKD remain to be assessed in future experimental studies beside miRNAs and TFs predicted. Furthermore, the functional analysis resulted in which most of them are expected to be associated with ADPKD pathogenesis, such as signal pathways that involved in cell growth, inflammation, and cell polarity. CONCLUSION:We have here explored systematic approaches for molecular mechanisms assay of ADPKD as a monogenic disease, which may also be used for other monogenetic diseases beside complex diseases to provide suitable therapeutic targets.

Dataset Information

Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.

Publications

Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.

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