Oxidative Stress and Genotoxicity Assessment in Pharmacological Models

Oxidative stress and genotoxicity constitute central concerns in the safety evaluation of pharmacological agents. Oxidative stress arises when the generation of reactive oxygen species (ROS) overwhelms endogenous antioxidant defences, leading to lipid peroxidation, protein oxidation and DNA damage. Genotoxicity assessment seeks to detect and quantify DNA lesions, chromosomal aberrations and mutagenic potential induced by candidate compounds. Pharmacological models span in vitro cell‐based assays to in vivo rodent studies, often integrating biochemical endpoints such as antioxidant enzyme activity, mitochondrial integrity and markers of oxidative DNA adducts. Advances in high‐throughput screening, molecular imaging and omics technologies have refined the detection of early oxidative insults and genotoxic events, facilitating mechanistic understanding. This integrative framework informs risk–benefit analyses for drug development, supports regulatory requirements and underpins the design of mitigation strategies to preserve genomic stability in patients.

Research from Nature Portfolio

Recent studies have elucidated how chronic exposure to a widely used quinoxaline derivative triggers oxidative damage in rodent liver. Detailed metabolomic analysis identified reductive metabolites that correlate with elevated ROS generation and protein carbonylation. Concurrent up-regulation of phase II detoxifying enzymes and activation of MAPK and Nrf2-Keap1 signalling pathways were observed, indicating an adaptive antioxidant response. This work delineates a metabolic pathway linking bioreductive activation to organ-specific toxicity and underscores the interplay between oxidative stress and genotoxic risk in vivo.

Oxidative Stress and Genotoxicity Assessment in Pharmacological Models publication trend

The graph below shows the total number of articles in oxidative stress and genotoxicity assessment in pharmacological models across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen, including superoxide and hydrogen peroxide, implicated in oxidative damage.

Genotoxicity: The capacity of a compound to damage genetic material, leading to mutations, chromosomal breaks or adduct formation.

Nrf2-Keap1 pathway: A cytoprotective signalling axis that regulates antioxidant gene expression in response to oxidative stress.

MAPK signalling: Mitogen-activated protein kinase cascades that transduce stress signals and regulate cell survival, apoptosis and gene expression.

Comet assay: A sensitive electrophoretic method for detecting DNA strand breaks at the level of individual cells.

References

1. Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox. Scientific Reports (2017).
2. Quercetin Attenuates Quinocetone-Induced Cell Apoptosis In Vitro by Activating the P38/Nrf2/HO-1 Pathway and Inhibiting the ROS/Mitochondrial Apoptotic Pathway. Antioxidants (2022).
3. Olaquindox‐Induced Liver Damage Involved the Crosstalk of Oxidative Stress and p53 In Vivo and In Vitro. Oxidative Medicine and Cellular Longevity (2020).
4. Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse. Frontiers in Pharmacology (2018).