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Published online before print March 22, 2007

0031-6997/07/5902-125-150$7.00
Pharmacol Rev 59:125-150, 2007

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Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase

Satori A. Marchitti, Richard A. Deitrich and Vasilis Vasiliou

Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado (S.A.M., V.V.); and Alcohol Research Center and Department of Pharmacology, University of Colorado Health Sciences Center at Fitzsimmons, School of Medicine, Aurora, Colorado (R.A.D.)

Abstract
I. Introduction
II. Aldehydes
    A. Biological Significance and Reactivity
    B. Biogenic Aldehydes
III. 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde in the Central Nervous System
    A. Intraneuronal Formation
    B. Transport Mechanisms
    C. Identification and Quantification in Biological Samples
IV. Toxicity of 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde in the Central Nervous System
    A. Cytotoxicity
    B. Protein Adduction
    C. Isoquinoline Formation
    D. Free Radical Generation
    E. Mechanisms of Apoptosis
    F. Potential Role in Neurodegeneration
V. Metabolism of 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde in the Central Nervous System
    A. Overview
    B. Aldehyde Dehydrogenase
        1. Human Aldehyde Dehydrogenases.
        2. Aldehyde Dehydrogenases Involved in 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde Metabolism.
        3. Role of Aldehyde Dehydrogenase Dysfunction.
    C. Alcohol Dehydrogenase
    D. Aldehyde and Aldose Reductase
    E. Downstream Metabolic Pathways
        1. Catechol-O-Methyltransferase.
        2. Phenolsulfotransferase.
        3. UDP-Glucuronosyltransferase.
VI. Concluding Remarks
Aldehydes are highly reactive molecules formed during the biotransformation of numerous endogenous and exogenous compounds, including biogenic amines. 3,4-Dihydroxyphenylacetaldehyde is the aldehyde metabolite of dopamine, and 3,4-dihydroxyphenylglycolaldehyde is the aldehyde metabolite of both norepinephrine and epinephrine. There is an increasing body of evidence suggesting that these compounds are neurotoxic, and it has been recently hypothesized that neurodegenerative disorders may be associated with increased levels of these biogenic aldehydes. Aldehyde dehydrogenases are a group of NAD(P)+-dependent enzymes that catalyze the oxidation of aldehydes, such as those derived from catecholamines, to their corresponding carboxylic acids. To date, 19 aldehyde dehydrogenase genes have been identified in the human genome. Mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, {gamma}-hydroxybutyric aciduria, and pyridoxine-dependent seizures, most of which are characterized by neurological abnormalities. Several pharmaceutical agents and environmental toxins are also known to disrupt or inhibit aldehyde dehydrogenase function. It is, therefore, possible to speculate that reduced detoxification of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde from impaired or deficient aldehyde dehydrogenase function may be a contributing factor in the suggested neurotoxicity of these compounds. This article presents a comprehensive review of what is currently known of both the neurotoxicity and respective metabolism pathways of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde with an emphasis on the role that aldehyde dehydrogenase enzymes play in the detoxification of these two aldehydes.

Address correspondence to: Dr. Vasilis Vasiliou, Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 E. 9th Ave., C238, Denver, CO 80262. E-mail: vasilis.vasiliou{at}uchsc.edu




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