Reactivation of zebrafish acetylcholinesterase by novel oxime compounds following inhibition by dichlorvos.
Author:
Hayden SchmidtMentors:
- Erica Fradinger, Assistant Professor of Biology, Whittier College
- Palmer Taylor, Dean, Skaggs School of Pharmacy and Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego
Organophosphates (OPs) covalently bind to the active site of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine at the cholinergic synapse, causing dysfunction of many physiological systems and in severe cases death. Currently, the oxime 2-PAM is used as a standard treatment for OP poisoning. We determined the inhibition kinetics of AChE by the organophosphate dichlorvos and compared the AChE reactivation kinetics of two novel oximes, RS-194B and RS-186B, to 2-PAM. Additionally, to evaluate the suitability of the zebrafish (Danio rerio) model system for in vivo tests, we compared the inhibition and reactivation kinetics from human AChE to zebrafish AChE isolated from tissue homogenates. For these studies, AChE activity was determined using the Ellman Assay. Dichlorvos inhibited both human and zebrafish AChE and this inhibition was rescued by all three oximes. Although the reactivation kinetics for 2-PAM were more efficient than those of RS-194B and RS-186B, results from the novel oximes indicate that they warrant further study in vivo. Additionally, zebrafish AChE demonstrated similar inhibition and reactivation kinetics to human AChE. Therefore, the zebrafish is an appropriate model system for the in vivo study of novel oxime AChE reactivators.