Theses and Dissertations

Advisor

Chambers, Janice

Committee Member

Ross, Matthew

Committee Member

Carr, Russel

Date of Degree

8-12-2026

Original embargo terms

Visible MSU Only 6 months

Document Type

Graduate Thesis - Campus Access Only

Major

Veterinary & Biomedical Science (Toxicology)

Degree Name

Master of Science (M.S.)

College

College of Veterinary Medicine

Department

Department of Comparative Biomedical Sciences

Abstract

Phorate (O,O-diethyl S-ethylthiomethyl phosphorodithioate) is an extremely lethal organophosphate insecticide that is bioactivated into highly toxic metabolites with potent anticholinesterase activity. Its mechanism of action involves phosphorylation of the active-site serine hydroxyl group of acetylcholinesterase (AChE), preventing hydrolysis of acetylcholine (ACh) into acetate and choline. The resulting accumulation of ACh causes overstimulation of muscarinic and nicotinic receptors, leading to hypercholinergic activity, glutamate-mediated excitotoxicity, seizures, respiratory distress, and death. Butyrylcholinesterase (BChE) hydrolyzes ACh and other choline and non-choline esters while also scavenging organophosphorus compounds, including insecticides. Oxime reactivators restore AChE activity by attacking the phosphorus atom bound to the active-site serine. However, phorate remains relatively understudied, and treatment relies on 2-PAM. Our novel oximes outperformed 2-PAM in reactivating PHO-sulfoxide-inhibited AChE as well as PHO-sulfoxide- and PHO-sulfone-inhibited BChE. These findings identify promising oxime candidates for improving treatment against phorate intoxication.

Sponsorship (Optional)

National Institutes of Health CounterACT grant R21NS108954

Download

Share

COinS