Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: Implications for the mechanism of enzyme inhibition

Erin M G Allen, David G R Anderson, Virginia R. Florang, May Khanna, Thomas Hurley, Jonathan A. Doorn

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Molinate is a thiocarbamate herbicide used as a pre-emergent in rice patty fields. It has two predominant sulfoxidation metabolites, molinate sulfoxide and molinate sulfone. Previous work demonstrated an in vivo decrease in liver aldehyde dehydrogenase (ALDH) activity in rats treated with molinate and motor function deficits in dogs dosed chronically with this compound. ALDH is an enzyme important in the catabolism of many neurotransmitters, such as dopamine. Inhibition of this enzyme may lead to the accumulation of endogenous neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde, a dopamine metabolite, which may account for the observed neurotoxicity. In this study, the relative reactivity of molinate and both of its sulfoxidation metabolites toward ALDH was investigated, as well as the mechanism of inhibition. The ALDH activity was monitored in two different model systems, human recombinant ALDH (hALDH2) and mouse striatal synaptosomes. Molinate sulfone was found to be the most potent ALDH inhibitor, as compared to molinate and molinate sulfoxide. The reactivity of these three compounds was also assessed, using N-acetyl Cys, model peptides, and hALDH2. It was determined that molinate sulfone is capable of covalently modifying Cys residues, including catalytic Cys302 of ALDH, accounting for the observed enzyme inhibition.

Original languageEnglish
Pages (from-to)1843-1850
Number of pages8
JournalChemical Research in Toxicology
Volume23
Issue number11
DOIs
StatePublished - Nov 15 2010

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Enzyme inhibition
Aldehyde Dehydrogenase
Metabolites
Enzymes
Sulfones
Dopamine
Thiocarbamates
Corpus Striatum
Synaptosomes
Herbicides
molinate
Liver
Neurotransmitter Agents
Rats
Dogs
Peptides

ASJC Scopus subject areas

  • Toxicology

Cite this

Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2 : Implications for the mechanism of enzyme inhibition. / Allen, Erin M G; Anderson, David G R; Florang, Virginia R.; Khanna, May; Hurley, Thomas; Doorn, Jonathan A.

In: Chemical Research in Toxicology, Vol. 23, No. 11, 15.11.2010, p. 1843-1850.

Research output: Contribution to journalArticle

Allen, Erin M G ; Anderson, David G R ; Florang, Virginia R. ; Khanna, May ; Hurley, Thomas ; Doorn, Jonathan A. / Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2 : Implications for the mechanism of enzyme inhibition. In: Chemical Research in Toxicology. 2010 ; Vol. 23, No. 11. pp. 1843-1850.
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