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Published on: October 21, 2017
CREB is a potential marker associated with drug-induced liver injury: Identification and validation through
Qiyue Zhang1, Shiori Taniguchi1, Kanako So2
1Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University.
Abstract:
Drug-induced liver injury (DILI) is the main cause of failure in drug development and postapproval withdrawal. Although toxicogenomic techniques provide an unprecedented opportunity for mechanistic assessment and biomarker discovery, they are not suitable for the screening of large numbers of exploratory compounds in early drug discovery. Using a comprehensive analysis of toxicogenomics (TGx) data, we aimed to find DILI-relevant transcription factors (TFs) that could be incorporated into a reporter gene assay system. Gene set enrichment analysis (GSEA) of the Open TG-GATEs dataset highlighted 4 DILI-relevant TFs, including CREB, NRF2, ELK-1, and E2F. Using ten drugs with already assigned idiosyncratic toxicity (IDT) risks, reporter gene assays were conducted in HepG2 cells in the presence of the S9 mix. There were weak correlations between NRF2 activity and IDT risk, whereas strong correlations were observed between CREB activity and IDT risk. In addition, CREB activation associated with 3 Withdrawn/Black box Warning drugs was reversed by pretreatment with a PKA inhibitor. Collectively, we suggest that CREB might be a sensitive biomarker for DILI prediction, and its response to stress induced by high-risk drugs might be primarily regulated by the PKA/CREB signaling pathway.
Insights
Drug-induced liver injury (DILI) is a major challenge in drug development. Researchers identified CREB as a sensitive biomarker for predicting DILI risk, potentially improving early drug discovery safety.
Area of Science:
- Pharmacology
- Toxicology
- Molecular Biology
Background:
- Drug-induced liver injury (DILI) is a significant hurdle in pharmaceutical development and post-market drug safety.
- Current toxicogenomic methods are effective for mechanistic studies but impractical for early-stage compound screening.
Purpose of the Study:
- To identify transcription factors (TFs) relevant to DILI from toxicogenomic data for reporter gene assay development.
- To evaluate the potential of identified TFs as predictive biomarkers for DILI risk.
Main Methods:
- Comprehensive analysis of toxicogenomics (TGx) data, including Gene Set Enrichment Analysis (GSEA) on the Open TG-GATEs dataset.
- Reporter gene assays in HepG2 cells using drugs with known idiosyncratic toxicity (IDT) risks and S9 mix.
- Investigated the role of the PKA/CREB signaling pathway in drug-induced stress responses.
Main Results:
- Gene Set Enrichment Analysis (GSEA) identified CREB, NRF2, ELK-1, and E2F as DILI-relevant transcription factors.
- CREB activity showed a strong correlation with idiosyncratic toxicity (IDT) risk, unlike NRF2.
- CREB activation by high-risk drugs was mitigated by PKA inhibitor pretreatment, suggesting PKA/CREB pathway involvement.
Conclusions:
- CREB demonstrates potential as a sensitive biomarker for predicting drug-induced liver injury (DILI).
- The PKA/CREB signaling pathway appears to be a key regulator of cellular response to DILI-inducing drugs.
