PUBLICATION

Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning

Authors
Sips, P.Y., Shi, X., Musso, G., Nath, A.K., Zhao, Y., Nielson, J., Morningstar, J., Kelly, A.E., Mikell, B., Buys, E., Bebarta, V., Rutter, J., Davisson, V.J., Mahon, S., Brenner, M., Boss, G.R., Peterson, R.T., Gerszten, R.E., MacRae, C.A.
ID
ZDB-PUB-180609-17
Date
2018
Source
PLoS One   13: e0193889 (Journal)
Registered Authors
Buys, Eva Plovie, MacRae, Calum A., Nath, Anjali, Peterson, Randall
Keywords
none
MeSH Terms
  • Animals
  • Metabolome/drug effects*
  • Metabolomics*
  • Potassium Cyanide/poisoning*
  • Pyruvate Dehydrogenase Complex/metabolism*
  • Swine
  • Zebrafish/metabolism*
  • Zebrafish Proteins/metabolism*
PubMed
29879736 Full text @ PLoS One
Abstract
Cyanide is a potent toxic agent, and the few available antidotes are not amenable to rapid deployment in mass exposures. As a result, there are ongoing efforts to exploit different animal models to identify novel countermeasures. We have created a pipeline that combines high-throughput screening in zebrafish with subsequent validation in two mammalian small animal models as well as a porcine large animal model. We found that zebrafish embryos in the first 3 days post fertilization (dpf) are highly resistant to cyanide, becoming progressively more sensitive thereafter. Unbiased analysis of gene expression in response to several hours of ultimately lethal doses of cyanide in both 1 and 7 dpf zebrafish revealed modest changes in iron-related proteins associated with the age-dependent cyanide resistance. Metabolomics measurements demonstrated significant age-dependent differences in energy metabolism during cyanide exposure which prompted us to test modulators of the tricarboxylic acid cycle and related metabolic processes as potential antidotes. In cyanide-sensitive 7 dpf larvae, we identified several such compounds that offer significant protection against cyanide toxicity. Modulators of the pyruvate dehydrogenase complex, as well as the small molecule sodium glyoxylate, consistently protected against cyanide toxicity in 7 dpf zebrafish larvae. Together, our results indicate that the resistance of zebrafish embryos to cyanide toxicity during early development is related to an altered regulation of cellular metabolism, which we propose may be exploited as a potential target for the development of novel antidotes against cyanide poisoning.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping