Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism

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Abstract

Aldehydes are highly reactive molecules that are intermediates or products involved in a broad spectrum of physiologic, biologic and pharmacologic processes. Aldehydes are generated from chemically diverse endogenous and exogenous precursors and aldehyde-mediated effects vary from homeostatic and therapeutic to cytotoxic, and genotoxic. One of the most important pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). Oxidation of the carbonyl functional group is considered a general detoxification process in that polymorphisms of several human ALDHs are associated a disease phenotypes or pathophysiologies. However, a number of ALDH-mediated oxidation form products that are known to possess significant biologic, therapeutic and/or toxic activities. These include the retinoic acid, an important element for vertebrate development, γ-aminobutyric acid (GABA), an important neurotransmitter, and trichloroacetic acid, a potential toxicant. This review summarizes the ALDHs with an emphasis on catalytic properties and xenobiotic substrates of these enzymes.

Introduction

It is generally accepted that the primary biotransformation reactions of Phase I and Phase II metabolism chemically modify various endogenous and exogenous substrates to more water-soluble intermediates or products which can then be readily eliminated. As specific substrates are chemically altered by these pathways, oxygen may be added and/or electrons are removed resulting in intermediates and products that are substantially more oxidized than the parent compound. For example, the addition of a hydroxyl group by cytochrome P450s is a common initial step in metabolism of a variety of compounds resulting in hydroxylated intermediates that are then substrates for subsequent oxidation(s) by various oxidoreductases such as alcohol and aldehyde dehydrogenases (ALDH; EC1.2.1.3). ALDHs are known to participate in oxidizing a plethora of endogenous and exogenous aldehydes [1]. Endogenous aldehydes are formed during the metabolism of amino acids, carbohydrates, lipids, biogenic amines, vitamins, and steroids. Biotransformation of a large number of drugs and environmental agents generates aldehydes. Aldehydes are highly reactive electrophilic compounds, which interact with thiol and amino groups and the aldehyde-mediated effects vary from physiologic and therapeutic to cytotoxic, genotoxic, and mutagenic or carcinogenic. In this respect, ALDHs efficiently oxidize and, in most instances, detoxify a significant number of chemically diverse aldehydes. Sixteen ALDH genes and three pseudogenes have been identified so far in the human genome with distinct chromosomal locations (Table 1). The importance of ALDHs in the detoxification pathways becomes evident from the polymorphisms of human ALDHs, which in most cases are associated with altered drug metabolism and disease phenotypes (reviewed in [2]). Polymorphism in ALDH2 is characterized by decreased acetaldehyde metabolism, low risk for alcoholism and increased risk for ethanol-induced cancers. Mutations in ALDH3A2, ALDH4A1, ALDH5A1 and ALDH6A1 appear to be the molecular basis for metabolic diseases characterized by neurologic manifestations. Mutations in ALDH3A2 are the molecular basis in Sjögren–Larsson syndrome and ALDH4A1 mutations predispose individuals to Type II hyperprolinemia. A deficiency in ALDH5A1 causes 4-hydroxybutyric aciduria, and lack of ALDH6A1 appears to be related with developmental delay. There are, however, instances where rather than producing a less toxic product, ALDHs catalyze reactions yielding chemically reactive or bioactive products that are detrimental to the organism. Formation of retinoic acid is the most intriguing function of ALDHs regarding bioactivation. Retinoic acid synthesis involves first the reversible oxidation of retinol (vitamin A) to retinal which is catalyzed by cytosolic alcohol dehydrogenases (ADHs) and/or microsomal retinol dehydrogenases, both of which belong to the short-chain dehydrogenase superfamily (e.g. 11-cis retinol dehydrogenase) [13]. Members of the ALDH superfamily then catalyze the irreversible oxidation retinal to retinoic acid. Whereas the light absorbing properties of retinal are a necessary element for vision, the carboxylic acid isomers all-trans-retinoic acid and/or 9-cis-retinoic acid serve as ligands for two families of retinoid nuclear receptors, the retinoic receptor (RAR) and the retinoid X receptor (RXR) that mediate gene expression for growth and development [4]. To date two ALDH enzymes, ALDH1A1 and ALDH1A2, have been studied in detail for their involvement in retinal oxidation. In addition, there is sufficient evidence that a third enzyme, ALDH1A3, also participates in the retinal oxidation to retinoic acid (reviewed in [3]). In mammalian species, γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter found in high concentration in brain and spinal cord and in trace amounts in peripheral tissues [5]. GABA is implicated in the control of the GABAergic, dopaminergic, and opioid systems. The main pathway for GABA synthesis is the decarboxylation of l-glutamate by l-glutamate decarboxylase. However, GABA can also be formed from putrescine by direct oxidative deamination catalyzed by diamine oxidase, to give γ-aminobutyraldehyde, which is then converted into GABA by an ALDH [6]. In addition, a second pathway involves the acetylation of putrescine to N-acetylputrescine, which is then converted into N-acetyl-γ-aminobutyraldehyde by monoamine oxidase. N-acetyl-γ-aminobutyraldehyde is converted to N-acetyl-GABA by ALDH followed by deacetylation to form GABA [7]. The enzyme that metabolizes of γ-aminobutyraldehyde and other amino aldehydes, namely ALDH9A1 (also known as E3) has been extensively studied by Piertruzsko and colleagues the last two decades [8].

ALDHs also produce potentially active metabolites during biotransformation of trichloroethelene. The initial metabolism of this chlorinated hydrocarbon is primarily by hepatic CYP2E1 and CYP1A2 to produce trichloroethanol [9]. Trichloroethanol is reduced to the corresponding aldehyde and trichloroacetic acid by alcohol and aldehyde dehydrogenase [10]. Whereas trichloroethylene and its metabolite chloral hydrate are not considered to be direct acting carcinogens [11], trichloroacetic acid is likely to be involved in the carcinogenic responses to this agent [12]. Further support for a mechanism of carcinogenesis involving trichloroethylene came from studies in which trichloroacetic acid induced exactly the same responses as trichloroethylene and caused liver tumors in mice at dose levels equivalent to the amount of trichloroacetic acid formed from trichloroethylene in vivo [11]. On the other hand, trichloroacetic acid appears to play a role in fetal cardiac teratogenesis when given to pregnant rats during organogenesis [13], [14]. In addition, it has recently been shown that trichloroacetic acid promotes the survival and growth of initiated cells [15]. Studies in rats indicate that cytosolic and mitochondrial ALDHs metabolize efficiently monochloroacetaldehyde and to a lesser extent dichloroacetaldehyde [16]. It is important to note that chloral hydrate is a potent competitive inhibitor of these enzymes [17].

Section snippets

ALDH gene superfamily

Gene superfamily is defined as a cluster of evolutionarily related sequences [18], and consists of homologous gene families, which are clusters of genes from different genomes that include both orthologs and paralogs [19]. Orthologs are genes in different species that evolved from a common ancestor by separation, whereas paralog genes are products of gene duplication events within the same genome. The ALDH gene superfamily is rather large and includes a variety of isozymes that can be

ALDH9A1

The ALDH9A1 gene codes for a cytosolic enzyme that has been extensively studied because of its potential involvement in the alternative biosynthesis of GABA. In this pathway, diamine oxidase deaminates 1,4-diaminobytarate to γ-aminobutyraldehyde, which is subsequently metabolized to GABA by ALDH9A1 [42]. ALDH9A1 cDNA/gene have been isolated and sequenced from human [8], rat and mouse [137]. The ALDH9A1 enzyme exhibits high affinity for aldehydes from generated diamines and polyamines (Km values

Conclusions

As noted, the ALDH superfamily is relatively large and contains a number of isozymes that have only recently been discovered. The presence of ALDH isoforms in a variety of tissues and subcellular fractions suggest that they play important roles in metabolism of endogenous and exogenous aldehydic substrates. The observations that certain of the ALDHs, such as ALDH1A1, participates in highly specific, non-catalytic interactions with androgens, thyroid hormone, flavopiridol and daunorubicin

Acknowledgements

We thank our colleagues for valuable discussions and a critical reading of this manuscript. This work was supported in part by NIH Grants R29 EY11490 & R01 AA11885 (VV) and R01 AA09300 (DRP) from the National Institutes of Health.

References (138)

  • X. Wang et al.

    Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli. Recognition of retinal as substrate

    J. Biol. Chem.

    (1996)
  • C. Graham et al.

    A retinaldehyde dehydrogenase as a structural protein in a mammalian eye lens. Gene recruitment of eta-crystallin

    J. Biol. Chem.

    (1996)
  • E.C. Swindell et al.

    Complementary domains of retinoic acid production and degradation in the early chick embryo

    Dev. Biol.

    (1999)
  • P. Penzes et al.

    Cloning of a rat cDNA encoding retinal dehydrogenase isozyme type I and its expression in E. coli

    Gene

    (1997)
  • L.C. Hsu et al.

    Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6

    Genomics

    (1994)
  • H. Li et al.

    A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse

    Mech. Dev.

    (2000)
  • L.C. Hsu et al.

    Cloning and characterization of a new functional human aldehyde dehydrogenase gene

    J. Biol. Chem.

    (1991)
  • M.J. Stewart et al.

    The novel aldehyde dehydrogenase gene, ALDH5, encodes an active aldehyde dehydrogenase enzyme

    Biochem. Biophys. Res. Commun.

    (1995)
  • R.J. Cook et al.

    Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase

    J. Biol. Chem.

    (1991)
  • S.A. Krupenko et al.

    Domain structure of rat 10-formyltetrahydrofolate dehydrogenase. Resolution of the amino-terminal domain as 10-formyltetrahydrofolate hydrolase

    J. Biol. Chem.

    (1997)
  • S.A. Krupenko et al.

    Expression, purification, and properties of the aldehyde dehydrogenase homologous carboxyl-terminal domain of rat 10-formyltetrahydrofolate dehydrogenase

    J. Biol. Chem.

    (1997)
  • S.A. Krupenko et al.

    Baculovirus expression and purification of rat 10-formyltetrahydrofolate dehydrogenase

    Protein Exp. Purif.

    (1995)
  • S.A. Krupenko et al.

    Aspartate 142 is involved in both hydrolase and dehydrogenase catalytic centers of 10-formyltetrahydrofolate dehydrogenase

    J. Biol. Chem.

    (1999)
  • T.R. Tephly

    The toxicity of methanol

    Life Sci.

    (1991)
  • L.C. Hsu et al.

    Genomic structure of the human cytosolic aldehyde dehydrogenase gene

    Genomics

    (1989)
  • L. Hjelmqvist et al.

    Class 2 aldehyde dehydrogenase. Characterization of the hamster enzyme, sensitive to daidzin and conserved within the family of multiple forms

    FEBS Lett.

    (1997)
  • S. Harada et al.

    Aldehyde dehydrogenase polymorphism and alcohol metabolism in alcoholics

    Alcohol

    (1985)
  • A. Yoshida et al.

    Molecular abnormality and cDNA cloning of human aldehyde dehydrogenases

    Alcohol

    (1985)
  • K. Kamino et al.

    Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population

    Biochem. Biophys. Res. Commun.

    (2000)
  • R.H. Wong et al.

    Effects on sister chromatid exchange frequency of aldehyde dehydrogenase 2 genotype and smoking in vinyl chloride workers

    Mutat. Res.

    (1998)
  • J. Farres et al.

    Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase. A model to study human (Oriental type) class 2 aldehyde dehydrogenase

    J. Biol. Chem.

    (1994)
  • J.S. Landin et al.

    Identification of a 54-kDa mitochondrial acetaminophen-binding protein as aldehyde dehydrogenase

    Toxicol. Appl. Pharmacol.

    (1996)
  • R. Lindahl et al.

    Lipid aldehyde oxidation as a physiological role for class 3 aldehyde dehydrogenases

    Biochem. Pharmacol.

    (1991)
  • M. Marselos et al.

    Substrate preference of a cytosolic aldehyde dehydrogenase inducible in rat liver by treatment with 3-methylcholanthrene

    Toxicol. Appl. Pharmacol.

    (1988)
  • D.C. Asman et al.

    Organization and characterization of the rat class 3 aldehyde dehydrogenase gene

    J. Biol. Chem.

    (1993)
  • L.C. Hsu et al.

    Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in Escherichia coli

    J. Biol. Chem.

    (1992)
  • J.S. Boesch et al.

    Constitutive expression of class 3 aldehyde dehydrogenase in cultured rat corneal epithelium

    J. Biol. Chem.

    (1996)
  • M. Abedinia et al.

    Bovine corneal aldehyde dehydrogenase: the major soluble corneal protein with a possible dual protective role for the eye

    Exp. Eye Res.

    (1990)
  • R. Lindahl

    Aldehyde dehydrogenases and their role in carcinogenesis

    Crit. Rev. Biochem. Mol. Biol.

    (1992)
  • V. Vasiliou et al.

    Polymorphisms of human aldehyde dehydrogenases: consequences for drug metabolism and disease

    Pharmacology

    (2000)
  • G. Duester

    Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid

    Eur. J. Biochem.

    (2000)
  • M. Mark et al.

    A genetic dissection of the retinoid signalling pathway in the mouse

    Proc. Nutr. Soc.

    (1999)
  • M. Malcangio et al.

    GABA and its receptors in the spinal cord

    Trends Pharmacol. Sci.

    (1996)
  • N. Seiler et al.

    4-Aminobutyrate in mammalian putrescine catabolism

    Biochem. J.

    (1975)
  • N. Seiler et al.

    Putrescine catabolism in mammalian brain

    Biochem. J.

    (1974)
  • A. Kikonyogo et al.

    Aldehyde dehydrogenase from adult human brain that dehydrogenates γ-aminobutyraldehyde: purification, characterization, cloning and distribution

    Biochem. J.

    (1996)
  • T. Nakajima et al.

    Cytochrome P450-related differences between rats and mice in the metabolism of benzene, toluene and trichloroethylene in liver microsomes

    Biochem. Pharmacol.

    (1993)
  • T. Green

    Tricholoethylene induced cancer in animals and its relevance to humans

    J. Occup. Health

    (1997)
  • J. Ashby et al.

    Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis

    Hum. Exp. Toxicol.

    (1994)
  • P.D. Johnson et al.

    A review: trichloroethylene metabolites: potential cardiac teratogens

    Environ. Health Perspect.

    (1998)
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