Organophosphates (OPs) are commonly found in commercial pesticides and are
highly toxic to humans if inhaled or ingested, resulting in both behavioural and
psychological symptoms. OPs chemically modify the essential protein acetylcholine
esterase, which is principally responsible for the breakdown of the essential
A group of investigators in the USA1 have developed a novel assay using the
model organism zebrafish (Danio rerio) for the screening of existing drug libraries
to identify compounds effective in the treatment of OP poisoning.The investigators
found that OP administration to zebrafish larvae induced similar symptoms to
those seen in humans, followed by death. The investigators used the prototypical
OP azinphos-methyl to screen 1200 known drugs in a 96-well plate format and
demonstrated that 16 of the drugs screened have a protective effect on the zebrafish
using a LC–MS–MS based metabolite profiling approach.
Acetylcholine is an essential neurotransmitter, acting as a chemical signal for the
transmission of information across synapses in the brain, undergoing formation and
breakdown cyclically. OPs act to block the breakdown of acetylcholine by blocking
the action of the enzyme, acetylcholine esterase. This blocking action results in an
unnatural accumulation of acetylcholine within the synapse, therefore inducing
continuous firing of signals resulting in behavioural and psychological symptoms.
The currently used antidote for OP poisoning is a combination of atropine and
pralidoxime (2-PAM); however, there are unacceptable risks of increased blood
pressure associated with treatment and so identifying new drugs is a priority.
The lead investigator of the study Dr Randall Peterson told The Column, “Humans
are confronted by all sorts of toxic chemicals through both accidental and intentional
exposures (such as chemotherapy). Our findings suggest that zebrafish could be used
to systematically screen for antidotes that are protective against organophosphate
exposure or virtually any other toxic chemical.”
1. S. Jin et al, Journal of Biomolecular Screening, DOI:10.1177/1087057112458153.
This story originally appeared in The Column. Click here to view that issue.