Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal

V.R Florang; J.N Rees; N.K Brogden; D.G Anderson; T.D Hurley; J.A Doorn

doi:10.1016/j.neuro.2006.07.018

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Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal

Journal article

Peer reviewed

Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal

V.R Florang, J.N Rees, N.K Brogden, D.G Anderson, T.D Hurley and J.A Doorn

Neurotoxicology (Park Forest South), Vol.28(1), pp.76-82

2007

DOI: 10.1016/j.neuro.2006.07.018

PMID: 16956664

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Abstract

Recent evidence indicates a role for oxidative stress and resulting products, e.g. 4-hydroxy-2-nonenal (4HNE) in the pathogenesis of Parkinson's disease (PD). 4HNE is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme very important to the dopamine (DA) metabolic pathway. DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. The biotransformation of DOPAL is critical as previous studies have demonstrated this DA-derived aldehyde to be a reactive electrophile and toxic to dopaminergic cells. Therefore, 4HNE produced via oxidative stress may inhibit ALDH2-mediated oxidation of the endogenous neurotoxin DOPAL. To test this hypothesis, ALDH2 in various model systems was treated with 4HNE and activity toward DOPAL measured. Incubation of human recombinant ALDH2 with 4HNE (1.5–30 μM) yielded inhibition of activity toward DOPAL. Furthermore, ALDH2 in rat brain mitochondrial lysate as well as isolated rat brain mitochondria was also sensitive to the lipid peroxidation product at low micromolar, as evident by a decrease in the rate of DOPAL to DOPAC conversion measured using HPLC. Taken together, these data indicate that 4HNE at low micromolar inhibits mitochondrial biotransformation of DOPAL to DOPAC, and generation of the lipid peroxidation product may represent a mechanism yielding aberrant levels of DOPAL, thus linking oxidative stress to the uncontrolled production of an endogenous neurotoxin relevant to PD.

Oxidative Stress

Dopamine metabolism

3,4-Dihydroxyphenylacetaldehyde (DOPAL)

4-Hydroxy-2-nonenal (4HNE)

Aldehyde dehydrogenase

Details

Title: Subtitle: Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal
Creators: V.R Florang - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA
J.N Rees - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA
N.K Brogden - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA
D.G Anderson - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA
T.D Hurley - Department of Biochemistry and Molecular Biology, University of Indiana School of Medicine, Indianapolis, IN 46202, USA
J.A Doorn - Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Neurotoxicology (Park Forest South), Vol.28(1), pp.76-82
Publisher: Elsevier B.V
DOI: 10.1016/j.neuro.2006.07.018
PMID: 16956664
ISSN: 0161-813X
eISSN: 1872-9711
Language: English
Date published: 2007
Academic Unit: Dermatology; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984025308302771

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