Jin, S., Sarkar, K.S., Jin, Y.N., Liu, Y., Kokel, D., Van Ham, T.J., Roberts, L.D., Gerszten, R.E., MacRae, C.A., and Peterson, R.T. (2013) An In Vivo Zebrafish Screen Identifies Organophosphate Antidotes with Diverse Mechanisms of Action. Journal of Biomolecular Screening. 18(1):108-115.
Organophosphates are a class of highly toxic chemicals that includes many pesticides and chemical weapons. Exposure to organophosphates,
either through accidents or acts of terrorism, poses a significant risk to human health and safety. Existing antidotes, in
use for over 50 years, have modest efficacy and undesirable toxicities. Therefore, discovering new organophosphate antidotes
is a high priority. Early life stage zebrafish exposed to organophosphates exhibit several phenotypes that parallel the human
response to organophosphates, including behavioral deficits, paralysis, and eventual death. Here, we have developed a high-throughput
zebrafish screen in a 96-well plate format to find new antidotes that counteract organophosphate-induced lethality. In a pilot
screen of 1200 known drugs, we identified 16 compounds that suppress organophosphate toxicity in zebrafish. Several in vitro
assays coupled with liquid chromatography/tandem mass spectrometry–based metabolite profiling enabled determination of mechanisms
of action for several of the antidotes, including reversible acetylcholinesterase inhibition, cholinergic receptor antagonism,
and inhibition of bioactivation. Therefore, the in vivo screen is capable of discovering organophosphate antidotes that intervene
in distinct pathways. These findings suggest that zebrafish screens might be a broadly applicable approach for discovering
compounds that counteract the toxic effects of accidental or malicious poisonous exposures.
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