Animal models of toxicology testing: the role of pigs

Helke, Kristi L.; Swindle, M. Michael

doi:10.1517/17425255.2013.739607

Cited by 95 publications

(62 citation statements)

References 92 publications

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“…The pig (swine) model is a large animal model used in a great number of laboratories and pharmaceutical research sites. The pig model has anatomical, physiological, and biochemical similarities to humans, and this model is considered a translational model in biomedical research and development [1]. The pig is specifically appropriate for the investigation of drug disposition since they have a significant number of membrane transport and enzymatic proteins in common with humans.…”

Section: Introductionmentioning

confidence: 99%

Minipigs as models in drug discovery

Singh

Thrall

Hauer‐Jensen

2016

Expert Opinion on Drug Discovery

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Section: Introductionmentioning

confidence: 99%

Minipigs as models in drug discovery

Singh

Thrall

Hauer‐Jensen

2016

Expert Opinion on Drug Discovery

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“…Pig can be regarded as a good model of extrapolation to humans (Helke and Swindle 2013). DON induces morphological injury (Osselaere et al 2013) and inflammation on porcine jejunum explants (Cano et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

et al. 2015

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Natural food contaminants such as mycotoxins are an important problem for human health. Deoxynivalenol (DON) is one of the most common mycotoxins detected in cereals and grains. Its toxicological effects mainly concern the immune system and the gastrointestinal tract. This toxin is a potent ribotoxic stressor leading to MAP kinase activation and inflammatory response. DON frequently co-occurs with its glucosylated form, the masked mycotoxin deoxynivalenol-3-β-D-glucoside (D3G). The toxicity of this later compound remains unknown in mammals. This study aimed to assess the ability of D3G to elicit a ribotoxic stress and to induce intestinal toxicity. The toxicity of D3G and DON (0-10 µM) was studied in vitro, on the human intestinal Caco-2 cell line, and ex vivo, on porcine jejunal explants. First, an in silico analysis revealed that D3G, contrary to DON, was unable to bind to the A-site of the ribosome peptidyl transferase center, the main targets for DON toxicity. Accordingly, D3G did not activate JNK and P38 MAPKs in treated Caco-2 cells and did not alter viability and barrier function on cells, as measured by the trans-epithelial electrical resistance. Treatment of intestinal explants for 4 h with 10 µM DON induced morphological lesions and up-regulated the expression of pro-inflammatory cytokines as measured by qPCR and pan-genomic microarray analysis. By contrast, expression profile of D3G-treated explants was similar to that of controls, and these explants did not show histomorphology alteration. In conclusion, our data demonstrated that glucosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity.

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“…The presence and activity of liver cytochrome P450 enzyme isoforms mediating phase I biotransformation (oxidation step) are comparable between pig, monkey, and man (reviewed in [150]). In addition, numerous data on similarities in further downstream biotransformation processes, such as conjugation reactions, have been reported [150,151]. Glomerular filtration rate and urine pH, which are important parameters for drug elimination, are similar in pigs and humans [152].…”

Section: Liver and Kidneymentioning

confidence: 99%