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Updated: Jun 22, 2025
The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice
Published on: February 3, 2012
Time-course cross-species transcriptomics reveals conserved hepatotoxicity pathways induced by repeated
Nguyen Tran Nam Tien1, Trinh Tam Anh1, Nguyen Thi Hai Yen1
1Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
Abstract:
Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate its underlying hepatotoxicity mechanism. This study aimed to capture the alterations in genome-wide expression over time and the subsequent perturbations of corresponding pathways across species. Six data from humans, mice, and rats, including animal liver tissue, human liver microtissues, and two liver cell lines exposed to CsA toxic dose, were used. The microtissue exposed to CsA for 10 d was analyzed to obtain dynamically differentially expressed genes (DEGs). Single-time points data at 1, 3, 5, 7, and 28 d of different species were used to provide additional evidence. Using liver microtissue-based longitudinal design, DEGs that were consistently up- or down-regulated over time were captured, and the well-known mechanism involved in CsA toxicity was elucidated. Thirty DEGs that consistently changed in longitudinal data were also altered in 28-d rat in-house data with concordant expression. Some genes (e.g. TUBB2A, PLIN2, APOB) showed good concordance with identified DEGs in 1-d and 7-d mouse data. Pathway analysis revealed up-regulations of protein processing, asparagine N-linked glycosylation, and cargo concentration in the endoplasmic reticulum. Furthermore, the down-regulations of pathways related to biological oxidations and metabolite and lipid metabolism were elucidated. These pathways were also enriched in single-time-point data and conserved across species, implying their biological significance and generalizability. Overall, the human organoids-based longitudinal design coupled with cross-species validation provides temporal molecular change tracking, aiding mechanistic elucidation and biologically relevant biomarker discovery.
Insights
Cyclosporine A (CsA) causes liver toxicity. This study tracked gene expression changes over time in human and animal models to reveal CsA
Area of Science:
- Toxicology
- Genomics
- Molecular Biology
Background:
- Cyclosporine A (CsA) is effective for immune diseases but causes liver toxicity.
- Understanding CsA hepatotoxicity mechanisms is crucial for safe clinical use.
Purpose of the Study:
- To investigate genome-wide expression alterations and pathway changes over time in response to CsA exposure.
- To elucidate the molecular mechanisms underlying CsA-induced hepatotoxicity across species.
Main Methods:
- Utilized longitudinal data from human liver microtissues and cross-species data (mice, rats) exposed to CsA.
- Identified dynamically differentially expressed genes (DEGs) and analyzed pathway perturbations.
- Validated findings using single-time point data and in-house rat data.
Main Results:
- Identified consistently up- or down-regulated DEGs over time in a longitudinal liver microtissue model.
- Pathway analysis revealed endoplasmic reticulum stress (protein processing, N-linked glycosylation) and altered metabolism (biological oxidations, lipid metabolism).
- Findings were conserved across human and animal models, indicating biological significance.
Conclusions:
- A human organoid-based longitudinal design coupled with cross-species validation effectively tracks temporal molecular changes.
- This approach aids in elucidating CsA hepatotoxicity mechanisms and discovering relevant biomarkers.
