Abstract
The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is detoxified mainly by aldehyde dehydrogenase (ALDH). We find that the fungicide benomyl potently and rapidly inhibits ALDH and builds up DOPAL in vivo in mouse striatum and in vitro in PC12 cells and human cultured fibroblasts and glial cells. The in vivo results resemble those noted previously with knockouts of the genes encoding ALDH1A1 and 2, a mouse model of aging-related Parkinson's disease (PD). Exposure to pesticides that inhibit ALDH may therefore increase PD risk via DOPAL buildup. This study lends support to the "catecholaldehyde hypothesis" that the autotoxic dopamine metabolite DOPAL plays a pathogenic role in PD.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3,4-Dihydroxyphenylacetic Acid / analogs & derivatives*
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3,4-Dihydroxyphenylacetic Acid / chemistry
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Aldehyde Dehydrogenase / antagonists & inhibitors
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Aldehyde Dehydrogenase / genetics
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Aldehyde Dehydrogenase / metabolism*
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Aldehydes / chemistry
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Aldehydes / toxicity
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Animals
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Antifungal Agents / chemistry
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Antifungal Agents / metabolism*
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Antifungal Agents / toxicity
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Benomyl / chemistry
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Benomyl / metabolism*
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Benomyl / toxicity
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Cell Line
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Humans
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Lipid Peroxidation / drug effects
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Mice
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PC12 Cells
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Parkinson Disease / etiology*
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Rats
Substances
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Aldehydes
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Antifungal Agents
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Enzyme Inhibitors
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3,4-Dihydroxyphenylacetic Acid
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3,4-dihydroxyphenylacetaldehyde
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Aldehyde Dehydrogenase
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4-hydroxy-2-nonenal
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Benomyl