Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility

Journal Article · Mon Jan 01 04:00:00 EST 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.10.008· OSTI ID:20976834

Gearhart, Debra A ^[1]; Sickles, Dale W ^[2]; Buccafusco, Jerry J ^[1]; Prendergast, Mark A ^[3]; Terry, Alvin V ^[1]

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1. Department of Pharmacology and Toxicology, 1120 Fifteenth Street, Medical College of Georgia, Augusta, GA 30912-2300 (United States)
2. Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912 (United States)
3. Department of Psychology, University of Kentucky Lexington, KY 40506 (United States)

Diisopropylfluorophosphate, originally developed as a chemical warfare agent, is structurally similar to nerve agents, and chlorpyrifos has extensive worldwide use as an agricultural pesticide. While inhibition of cholinesterases underlies the acute toxicity of these organophosphates, we previously reported impaired axonal transport in the sciatic nerves from rats treated chronically with subthreshold doses of chlorpyrifos. Those data indicate that chlorpyrifos (and/or its active metabolite, chlorpyrifos-oxon) might directly affect the function of kinesin and/or microtubules-the principal proteins that mediate anterograde axonal transport. The current report describes in vitro assays to assess the concentration-dependent effects of chlorpyrifos (0-10 {mu}M), chlorpyrifos-oxon (0-10 {mu}M), and diisopropylfluorophosphate (0-0.59 nM) on kinesin-dependent microtubule motility. Preincubating bovine brain microtubules with the organophosphates did not alter kinesin-mediated microtubule motility. In contrast, preincubation of bovine brain kinesin with diisopropylfluorophosphate, chlorpyrifos, or chlorpyrifos-oxon produced a concentration-dependent increase in the number of locomoting microtubules that detached from the kinesin-coated glass cover slip. Our data suggest that the organophosphates-chlorpyrifos-oxon, chlorpyrifos, and diisopropylfluorophosphate-directly affect kinesin, thereby disrupting kinesin-dependent transport on microtubules. Kinesin-dependent movement of vesicles, organelles, and other cellular components along microtubules is fundamental to the organization of all eukaryotic cells, especially in neurons where organelles and proteins synthesized in the cell body must move down long axons to pre-synaptic sites in nerve terminals. We postulate that disruption of kinesin-dependent intracellular transport could account for some of the long-term effects of organophosphates on the peripheral and central nervous system.

• OSTI ID: 20976834
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 218; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BRAIN
CATTLE
CHEMICAL WARFARE AGENTS
CHOLINESTERASE
IN VITRO
MICROTUBULES
NERVE CELLS
NERVES
PESTICIDES
RATS
TOXICITY