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

Debra A. Gearhart, Dale W. Sickles, Jerry J. Buccafusco, Mark A. Prendergast, Alvin V Terry

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 μM), chlorpyrifos-oxon (0-10 μM), 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.

Original languageEnglish (US)
Pages (from-to)20-29
Number of pages10
JournalToxicology and Applied Pharmacology
Volume218
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Isoflurophate
Chlorpyrifos
Kinesin
Microtubules
Organophosphates
Axonal Transport
Organelles
Brain
Chemical Warfare Agents
Microtubule Proteins
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate
Cholinesterases
Peripheral Nervous System
Neurology
Eukaryotic Cells
Sciatic Nerve
Metabolites
Pesticides
Neurons
Glass

Keywords

  • Axonal transport
  • Chlorpyrifos
  • Chlorpyrifos-oxon
  • Cholinesterase
  • DFP
  • Diisopropylfluorophosphate
  • Kinesin
  • Kinesin superfamily (KIF)
  • Microtubule motility
  • Microtubules
  • Organophosphates
  • Organophosphorus
  • Pesticides
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility. / Gearhart, Debra A.; Sickles, Dale W.; Buccafusco, Jerry J.; Prendergast, Mark A.; Terry, Alvin V.

In: Toxicology and Applied Pharmacology, Vol. 218, No. 1, 01.01.2007, p. 20-29.

Research output: Contribution to journalArticle

Gearhart, Debra A. ; Sickles, Dale W. ; Buccafusco, Jerry J. ; Prendergast, Mark A. ; Terry, Alvin V. / Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility. In: Toxicology and Applied Pharmacology. 2007 ; Vol. 218, No. 1. pp. 20-29.
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