Animal Models in Pharmacogenomics

Olson, Erin; Graham, Delyth

doi:10.1016/b978-0-12-386882-4.00005-0

Cited by 9 publications

(8 citation statements)

References 85 publications

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“…This likely account for the fact that the substance is a weak inducer of the Rtkn genotoxicity reporter. ENU is a weak‐acting alkylating agent that transfers its ethyl group to nitrogen or oxygen in DNA, resulting in base mispairing that causes base‐pair substitution mutations (Dobo et al, 2011; Olson & Graham, 2014). The ethyl group of EMS is transferred to guanine forming O 6 ‐ethylguanine; the unrepaired adduct can lead to mutations, cell cycle arrest, or apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Quantitative interpretation of ToxTracker dose–response data for potency comparisons and mode‐of‐action determination

Boisvert

Derr

Østerlund

et al. 2023

Environ and Mol Mutagen

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ToxTracker is an in vitro mammalian stem cell-based reporter assay that detects activation of specific cellular signaling pathways (DNA damage, oxidative stress, and/or protein damage) upon chemical exposure using flow cytometry. Here we used quantitative methods to empirically analyze historical control data, and dose-response data across a wide range of reference chemicals. First, we analyzed historical control data to define a fold-change threshold for identification of a significant positive response. Next, we used the benchmark dose (BMD) combined-covariate approach for potency ranking of a set of more than 120 compounds; the BMD values were used for comparative identification of the most potent inducers of each reporter.

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Section: Discussionmentioning

confidence: 99%

Quantitative interpretation of ToxTracker dose–response data for potency comparisons and mode‐of‐action determination

Boisvert

Derr

Østerlund

et al. 2023

Environ and Mol Mutagen

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“…They were housed in controlled conditions of humidity, temperature (22°C), 12/12h light-dark cycle, and commercial diet and water ad libitum . This murine model was chosen because it does not show consanguinity, similarly to humans [ 19 , 20 ], and because female mice seem to be more sensitive to develop allergic inflammations [ 21 , 22 ]. All procedures were approved by the Ethics Committee for Use in Animals ( Comitê de Ética para Uso em Animais –CEUA, State University of Ceará, no.…”

Section: Methodsmentioning

confidence: 99%

Anti-asthmatic effect of nitric oxide metallo-donor FOR811A [cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3] in the respiratory mechanics of Swiss mice

et al. 2021

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We aimed at evaluating the anti-asthmatic effect of cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3 (FOR811A), a nitrosyl-ruthenium compound, in a murine model of allergic asthma. The anti-asthmatic effects were analyzed by measuring the mechanical lung and morphometrical parameters in female Swiss mice allocated in the following groups: untreated control (Ctl+Sal) and control treated with FOR811A (Ctl+FOR), along asthmatic groups untreated (Ast+Sal) and treated with FOR811A (Ast+FOR). The drug-protein interaction was evaluated by in-silico assay using molecular docking. The results showed that the use of FOR811A in experimental asthma (Ast+FOR) decreased the pressure-volume curve, hysteresis, tissue elastance, tissue resistance, and airway resistance, similar to the control groups (Ctl+Sal; Ctl+FOR). However, it differed from the untreated asthmatic group (Ast+Sal, p<0.05), indicating that FOR811A corrected the lung parenchyma and relaxed the smooth muscles of the bronchi. Similar to control groups (Ctl+Sal; Ctl+FOR), FOR811A increased the inspiratory capacity and static compliance in asthmatic animals (Ast+Sal, p<0.05), showing that this metallodrug improved the capacity of inspiration during asthma. The morphometric parameters showed that FOR811A decreased the alveolar collapse and kept the bronchoconstriction during asthma. Beyond that, the molecular docking using FOR811A showed a strong interaction in the distal portion of the heme group of the soluble guanylate cyclase, particularly with cysteine residue (Cys141). In summary, FOR811A relaxed bronchial smooth muscles and improved respiratory mechanics during asthma, providing a protective effect and promising use for the development of an anti-asthmatic drug.

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“…The main advantages of outbred mice are their incomparable genetic diversity and low cost. However, there are some disadvantages of outbred mice as an experimental model: a large number of animals are required to maintain statistical power due to genetic diversity, and they are “genetically undefined”, meaning the genotype of an individual is unknown ( Olson and Graham, 2014 ). Diversity Outbred (DO) mice are a new outbred mouse population derived from the same eight founder strains as the Collaborative Cross (CC) inbred strains ( Collaborative Cross, 2012 ; Svenson et al., 2012 ) and retain the same set of genetic variants as CC mice ( Churchill et al., 2004 ; Svenson et al., 2012 ; Smith et al., 2016 ).…”

Section: Mice: the Workhorses For Initial Compound Characterizationmentioning

confidence: 99%

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

Yang

Wang

Wen

et al. 2021

Front. Cell. Infect. Microbiol.

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Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a small proportion harbor Mycobacterium tuberculosis (Mtb) strains that have become resistant to drugs in the standard regimen. Development and approval of new drugs for TB have accelerated in the last 10 years, but more drugs are needed due to both Mtb’s development of resistance and the desire to shorten therapy to 4 months or less. The drug development process needs predictive animal models that recapitulate the complex pathology and bacterial burden distribution of human disease. The human host response to pulmonary infection with Mtb is granulomatous inflammation usually resulting in contained lesions and limited bacterial replication. In those who develop progressive or active disease, regions of necrosis and cavitation can develop leading to lasting lung damage and possible death. This review describes the major vertebrate animal models used in evaluating compound activity against Mtb and the disease presentation that develops. Each of the models, including the zebrafish, various mice, guinea pigs, rabbits, and non-human primates provides data on number of Mtb bacteria and pathology resolution. The models where individual lesions can be dissected from the tissue or sampled can also provide data on lesion-specific bacterial loads and lesion-specific drug concentrations. With the inclusion of medical imaging, a compound’s effect on resolution of pathology within individual lesions and animals can also be determined over time. Incorporation of measurement of drug exposure and drug distribution within animals and their tissues is important for choosing the best compounds to push toward the clinic and to the development of better regimens. We review the practical aspects of each model and the advantages and limitations of each in order to promote choosing a rational combination of them for a compound’s development.

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Animal Models in Pharmacogenomics

Cited by 9 publications

References 85 publications

Quantitative interpretation of ToxTracker dose–response data for potency comparisons and mode‐of‐action determination

Quantitative interpretation of ToxTracker dose–response data for potency comparisons and mode‐of‐action determination

Anti-asthmatic effect of nitric oxide metallo-donor FOR811A [cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3] in the respiratory mechanics of Swiss mice

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

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