Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends
Abstract
:1. Introduction
1.1. Adverse Outcome Pathways vs. Pathways of Toxicity
1.2. Metabolomics to Understand Human Exposure Contributions to Disease and Treatment Efficacy
2. Metabolomics Data Quality Assurance in Preclinical Drug Safety Assessment
3. Role of Metabolomics in Toxicology
4. State of the Art of Metabolomics in Toxicology
5. Future Trends in Metabolomics for Toxicology
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound/Substance and Model | Mechanistic Insights | Biomarkers Identified | References |
---|---|---|---|
Acetaminophen (APAP) in rats | Mitochondrial oxidative and nitrosative stress; bile acid metabolism changes | cysteine-glutathione disulfide | [56,57,58,59] |
Cigarette smoke in lung cells | Disruption of glycolysis, Krebs cycle, choline metabolism, and additive oxidative stress | glucose↓ lactate↑ Δ fumarate/malate | [60,61,62] |
35 test substances in liver cells | Patterns of liver enzyme induction/inhibition, liver toxicity, and peroxisome proliferation | diverse | [63] |
MPP+ in neurons | Dopaminergic neuron death pathways | diverse | [64] |
Liver toxicants in rats | Early metabolomic changes | amino acids, bile acids↑; | [65] |
Kidney toxicants in rats | Early metabolomic changes | Δ TCA cycle; urinary 2-oxoglutarate↑ | [65,66] |
Phenoxy herbicides in rats | Liver and kidney toxicity | Diverse pattern | [67] |
2- and 3-aminopropanol in rats | Similarity of compounds allowing read-across | Diverse pattern | [68] |
Spironolactone in fathead minnows | Changes in liver linked to declines in fecundity and other reproductive-related endpoints | Δ amino acid, tryptophan, and fatty acid metabolism | [3] |
Dioxin-exposed humans vs. control | Distinct metabolite profiles | 24 urinary steroid-related biomarkers | [69] |
Tributyltin in zebrafish | Affected steroid biosynthesis metabolism | Diverse | [70,71] |
6-propyl-2-thiouracil in zebrafish | (Neuro-) developmental toxicity | methionine↓, tyrosine↑, pipecolic acid↑ and lysophosphatidylcholine↑ | [72] |
Arecoline in rats | Δ lipid metabolism, amino acid metabolism, and vitamin metabolism | Δ D-Lysine, N4-Acetylaminobutanal, and L-Arginine | [73] |
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Sillé, F.; Hartung, T. Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends. Metabolites 2024, 14, 98. https://doi.org/10.3390/metabo14020098
Sillé F, Hartung T. Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends. Metabolites. 2024; 14(2):98. https://doi.org/10.3390/metabo14020098
Chicago/Turabian StyleSillé, Fenna, and Thomas Hartung. 2024. "Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends" Metabolites 14, no. 2: 98. https://doi.org/10.3390/metabo14020098