PUBLICATION
Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system
- Authors
- Schmidt, H.R., Radić, Z., Taylor, P., Fradinger, E.A.
- ID
- ZDB-PUB-150224-15
- Date
- 2015
- Source
- Toxicology and applied pharmacology 284(2): 197-203 (Journal)
- Registered Authors
- Fradinger, Erica
- Keywords
- Aldoxime antidotes, Chlorpyrifos oxon, Dichlorvos, Organophosphate, Zebrafish
- MeSH Terms
-
- Acetylcholinesterase/metabolism
- Animals
- Antidotes/pharmacology*
- Chemical Warfare Agents/toxicity*
- Cholinesterase Inhibitors/toxicity
- Cholinesterase Reactivators/pharmacology
- Embryo, Nonmammalian/drug effects
- Humans
- Kinetics
- Organophosphate Poisoning/drug therapy*
- Organophosphorus Compounds/antagonists & inhibitors*
- Organophosphorus Compounds/toxicity*
- Oximes/pharmacology*
- Zebrafish
- PubMed
- 25701203 Full text @ Tox. App. Pharmacol.
Citation
Schmidt, H.R., Radić, Z., Taylor, P., Fradinger, E.A. (2015) Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system. Toxicology and applied pharmacology. 284(2):197-203.
Abstract
The zebrafish is rapidly becoming an important model system for screening of new therapeutics. Here we evaluated the zebrafish as a potential pharmacological model for screening novel oxime antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE). The ki values determined for chlorpyrifos oxon (CPO) and dichlorvos (DDVP) showed that CPO was a more potent inhibitor of both human and zebrafish AChE, but overall zebrafish AChE was less sensitive to OP inhibition. In contrast, aldoxime antidotes, the quaternary ammonium 2-PAM and tertiary amine RS-194B, showed generally similar overall reactivation kinetics, kr, in both zebrafish and human AChE. However, differences between the Kox and k2 constants suggest that zebrafish AChE associates more tightly with oximes, but has a slower maximal reactivation rate than human AChE. Homology modeling suggests that these kinetic differences result from divergences in the amino acids lining the entrance to the active site gorge. Although 2-PAM had the more favorable in vitro reactivation kinetics, RS-194B was more effective antidote in vivo. In intact zebrafish embryos, antidotal treatment with RS-194B rescued embryos from OP toxicity, whereas 2-PAM had no effect. Dechorionation of the embryos prior to antidotal treatment allowed both 2-PAM and RS-194B to rescue zebrafish embryos from OP toxicity. Interestingly, RS-194B and 2-PAM alone increased cholinergic motor activity in dechorionated embryos possibly due to the reversible inhibition kinetics, Ki and αKi, of the oximes. Together these results demonstrate that the zebrafish at various developmental stages provides an excellent model for investigating membrane penetrant antidotes to OP exposure.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping