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Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle.pdf (1.69 MB)

Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle.

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journal contribution
posted on 2018-04-24, 11:58 authored by William Dott, Jayne Wright, Kelvin Cain, Pratibha Mistry, Karl E. Herbert
There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored using in vitro L6 metabolic models. These models demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle models to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.

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Citation

Redox Biology, 2017, 14, pp. 198-210

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

Redox Biology

Publisher

Elsevier

eissn

2213-2317

Acceptance date

2017-09-13

Copyright date

2017

Available date

2018-04-24

Publisher version

https://www.sciencedirect.com/science/article/pii/S2213231717303476?via=ihub#!

Language

en

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