Role of aldehyde dehydrogenases in physiopathological processes

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Role of aldehyde dehydrogenases in physiopathological processes José Salud Rodríguez-Zavala, Luis Francisco Calleja, Rafael Moreno-Sánchez, and Belem Yoval-Sánchez Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00256 • Publication Date (Web): 10 Jan 2019 Downloaded from http://pubs.acs.org on January 12, 2019

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Chemical Research in Toxicology

Role of aldehyde dehydrogenases in physiopathological processes José Salud Rodríguez-Zavala, Luis Francisco Calleja, Rafael Moreno-Sánchez and Belem Yoval-Sánchez*. Departamento de Bioquímica, Instituto Nacional de Cardiología, México D.F., México. Correspondence to: B. Yoval-Sánchez, Ph. D. Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Sección XVI, Tlalpan 14080, Ciudad de México, México Fax: +52 555 573 2911 Tel: +52 555 573 0926 e-mail:[email protected]

Key Words: aldehyde dehydrogenases, lipoperoxidation, lipid aldehydes, 4hydroxy-2-nonenal, oxidative stress.

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Table of content graphic

e-

O2

ROS

Oxidative Stress

Lipid Peroxidation

High toxicity MDA 2-alkenals 4-HNE

Pathologies

+ Low toxicity

ALDHs

Carboxylicxacid

ALDH-activator

Carboxylic acid

2


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Abstract Many different diseases are associated to oxidative stress.

One of the main

consequences of oxidative stress at the cellular level is lipid peroxidation, from which toxic aldehydes may be generated. Below their toxicity thresholds, some aldehydes are involved in signaling processes, while others are intermediaries in the metabolism of lipids, amino acids, neurotransmitters and carbohydrates. Some aldehydes ubiquitously distributed in the environment such as acrolein or formaldehyde are extremely toxic to the cell.

On the other hand, aldehyde

dehydrogenases (ALDHs) are able to detoxify a wide variety of aldehydes to their corresponding carboxylic acids thus helping to protect from oxidative stress. ALDHs are located in different subcellular compartments such as cytosol, mitochondria, nucleus and endoplasmic reticulum. The aim of this review is to analyze, and highlight, the role of different ALDH isoforms in the detoxification of aldehydes generated in processes that involve high levels of oxidative stress. The ALDH physiological relevance becomes evident by the observation that their expression and activity are enhanced in different pathologies that involve oxidative stress such as neurodegenerative disorders, cardiopathies, atherosclerosis and cancer, as well as inflammatory processes. Furthermore, ALDH mutations bring about several disorders in the cell. Thus, understanding the mechanisms by which these enzymes participate in diverse cellular processes may lead to better contend with the damage caused by toxic aldehydes in different pathologies by designing modulators and / or protocols to modify their activity or expression.

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Introduction The number of reports involving the participation of aldehyde dehydrogenases (ALDHs) in the etiology of different diseases has increased in recent years, highlighting the importance of these enzymes in the cell. In humans, 19 functional protein-coding genes of ALDHs have been described. These enzymes are widely distributed in the organism, playing different roles according to their specificity for substrates and are critical for certain physiological and pathological processes, since they regulate the concentration of aldehydes in the cell, by oxidizing them to the corresponding less reactive and more soluble acids in a NAD(P)+ dependent reaction. By preventing the accumulation of aldehydes derived from endogenous or exogenous processes, ALDHs mitigate oxidative damage at the cellular and tissue levels1, 2. Diverse isoforms of ALDHs are able to detoxify aldehydes generated as byproducts of lipoperoxidation (Fig. 1), such as 4-hydroxy-2-nonenal (4-HNE), 4hydroxy-2-hexenal (4-HHE), malondialdehyde (MDA) and acrolein with different degrees of specificity, preventing or attenuating the cell damage generated by these molecules. However, ALDHs may become inactivated by lipid aldehydes. Indeed, the susceptibility to lipid peroxidation byproducts of three human ALDH isoforms (ALDH1A1, ALDH2 and ALDH3A1) was recently reported3.

It was

observed that ALDH3A1 was insensitive to inactivation when exposed to high concentrations of these aldehydes (> 300 M HNE and > 20 mM acrolein), while ALDH1A1 and ALDH2, that have high catalytic efficiencies with these compounds, were inactivated at low concentrations (< 10 M). The differences in susceptibility 4


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to lipid aldehydes correlated with the content of cysteines (Cys) in the catalytic site, since ALDH3A1 only has the catalytic Cys, while ALDH1A1 and ALDH2 have 1 and 2 Cys adjacent to the catalytic Cys, respectively. Thus, adducts formation and the consequent inactivation is favored in these last two isoforms3.

Figure. 1. Structure of the most representative aldehydes byproducts of lipid peroxidation.

Drawing

ACD\ChemSketch

of

structures

was

made

with

the

software

(https://www.acdlabs.com/resources/freeware/chemsketch/)4.

The panel of three-dimensional structures of aldehydes was prepared using PyMOL (The PyMOL Molecular Graphics System, Version 1.3; Schrodinger, LLC; http://pymol.sourceforge.net/). 5



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ALDHs inactivation may interfere with the efficient detoxification of lipid aldehydes, promoting their accumulation, which may trigger ROS production and then further lipoperoxidation, amplifying oxidative damage in the cell (Fig. 2). In this regard, it has been established that mutations in ALDHs genes leading to defective aldehydes metabolism are the molecular basis of several diseases, including hydroxybutiric aciduria, pyridoxine-dependent seizures, Sjögren-Larson syndrome, type II hyperprolinemia, and may even contribute to the etiology of complex diseases including cancer, Parkinson and Alzheimer2. It has been determined that an ALDH2 polymorphism where glutamate at position 487 is replaced by a lysine generates a less active enzyme form5.

This

polymorphism promotes the accumulation of acetaldehyde, as well as other endogenous toxic aldehydes in ethanol drinkers, which in turn may favor the development of cardiopathies or some types of cancer6, 7. Then, it is important to identify or design molecules with the ability to protect and stabilize ALDH activity to contribute to attenuate the effects of oxidative stress. In the present review, we describe and analyze the physiological consequences of the oxidative stress linked-accumulation of different aldehydes in the cell and discuss the contribution and roles of ALDHs in several pathologies.

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Necrosis

endogenous CYP 450 NADPH oxidase Cyclooxygenase Xanthine oxidase

Mitochondrial disfunction (Respiratory chain)

Pathologies Apoptosis

Lipid peroxidation

ROS

Formation of adducts

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


UV/ radiation Xenobiotics exogenous Proteins DNA

Carboxylic acid low toxicity

MDA 2-alkenals 4-HNE

ALDH NAD(P)H

NAD(P)+

Formation of adducts

high toxicity

Figure 2. Generation of ROS induces lipid peroxidation, and its byproducts may inhibit ALDHs, which in turn triggers accumulation of toxic aldehydes and promotes higher levels of ROS, amplifying cellular oxidative damage.

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Anti-oxidant cellular response Generation of ROS during events of oxidative stress can cause severe damage to macromolecules, including membrane phospholipids, nucleic acids and proteins. To prevent this damage cells use a variety of antioxidant molecules that react directly with oxidant agents neutralizing them8; these antioxidant compounds are known as ROS scavengers.

Vitamin E (-tocopherol) is the major antioxidant

bound to membranes whereas vitamin C (ascorbic acid) is one of the main antioxidant in the aqueous phase. The fact that these two antioxidants are human vitamins (i.e., they can only be acquired through the diet) emphasizes their crucial role in maintaining health. Other important cellular antioxidant compounds are carotene and ubiquinone (lipophilic), and uric acid, glutathione and ceruloplasmin (water-soluble). Cells also synthesize numerous antioxidant enzymes to manage and minimize the damage by oxidative stress.

One of the most studied enzymes is superoxide

dismutase (SOD) that catalyzes the reaction O2●- + O2●- + 2H+ to H2O2 + O2. All members of the SOD family use transition metals in their active site. Bacteria have Fe-SOD and Mn-SOD, whereas mammalian cells use different cytosolic and extracellular forms of Cu/Zn-SOD and mitochondrial Mn-SOD, which is closely related to the Mn-SOD of bacteria9. In mammalian cells the SOD product H2O2 is quickly removed by two families of enzymes: glutathione peroxidases (GPXs) and catalases. Both, GPX and catalase detoxify H2O2 by reducing it to water and O2. GPXs use the reducing potential of glutathione (GSH). In the reduction of one 8


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molecule of hydrogen peroxide, two GSH molecules are oxidized to form a compound with a disulfide bond (GS-SG). The enzyme glutathione reductase (GR) uses NADPH to re-reduce one molecule of GS-SG to two reduced GSH molecules, to allow the continuous action of GPXs9. Cys residues in proteins are important targets of oxidative stress, since the thiol group is highly susceptible to auto-oxidation and metal-catalyzed oxidation. Disulfide bonds formed between two proteins promote the generation of supramolecular assemblies resulting in inactivated enzymes; this phenomenon is known as intermolecular crosslinking. Thus, a major repair process in the cell is the re-reduction of oxidized sulfhydryl groups in proteins.

Another deleterious

process of proteins is the oxidation of methionine residues to methionine sulfoxide, which can cause the loss of enzyme function. The enzyme methionine sulfoxide reductase can regenerate methionine residues within oxidized proteins and restore their function9. It is well known that oxidized proteins are recognized and degraded by proteases to amino acids and replaced by de novo synthesis of proteins10-12. Under

certain

conditions,

antioxidant

protection

systems

may

become

overwhelmed. Then, as a result, cellular damage by high ROS levels may induce lipid peroxidation and lipid aldehydes accumulation, which play a crucial role in the pathogenesis of various chronic and acute diseases such as cancer, inflammation, liver damage, rheumatoid arthritis and atherosclerosis, among others 13.

It has

been reported that a single free oxygen radical initiation event can be rapidly propagated to damage 200 to 400 lipid molecules generating high levels of lipid 9



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aldehydes, before the slower reaction of two radicals to eliminate the unpaired electrons takes place and terminates the reaction sequence14. These events promote increased levels of protein adducts with aldehydes; these conjugates have been found in all mammalian tissues and their abundance increases in pathologies related with aging15.

Aldehydes: sources and metabolism. Environmental Pollution. Aldehydes are organic compounds containing carbonyl groups which are highly reactive and cytotoxic. These compounds are ubiquitously distributed in the environment and hence they can be acquired from different sources like food, water and air, or can be generated during physiological processes from a wide variety of endogenous and exogenous precursors. More than 300 different aldehydes have been identified in food and the estimated daily intake of unsaturated aldehydes from the diet in humans is 5 mg/kg, while total aldehydes consumption (unsaturated and saturated) is approximately 7 mg/kg. At least 36 different aldehydes can be found in water and, after heavy metals, these compounds are considered the major pollutants in drinking water. Several aldehydes including formaldehyde, acetaldehyde and acrolein are generated from industrial activity or produced during the incomplete combustion of organic materials and are also present in polluted air and cigarette smoke. It has been estimated that on average an adult human living in a big city inhales 26 g of

10


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acrolein/day from the environment. Motorized vehicles represent the main source of pollution by aldehydes, through direct emission and by the emission of noncombusted hydrocarbons, which subsequently derive in aldehydes16-19. Biological Functions. In many foods, aliphatic and aromatic aldehydes including citral, benzaldehyde, acetaldehyde and formaldehyde, are found providing taste and odor, particularly in fruits and vegetables20. In animals, some aldehydes such as acrolein, benzaldehyde, and hexanal may act as communication or signaling molecules and have roles in attraction or defense mechanisms21.

Many aldehydes are also generated as physiopathological

intermediaries during the biotransformation of endogenous compounds, including lipids, amino acids, carbohydrates and neurotransmitters and although some are essential for normal biological processes, many are cytotoxic and even carcinogenic (Table 1). For instance, from lipoperoxidation more than 200 species of aldehydes including 4-HHE, 4-HNE, MDA and acrolein are produced (Fig. 1)22. 4-HNE is the most reactive and cytotoxic aldehyde product of lipid peroxidation. This aldehyde causes a variety of effects in biological systems, for example, induces GSH depletion, inhibits the DNA and RNA synthesis, impairs mitochondrial respiration and induces morphological changes in these organelles23-25.

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Figure 3. Different roles of aldehydes in the organism. Aldehydes participate in several cellular processes in a concentration dependent manner.

Due to their

hormetic effects, aldehydes are able to modulate different antioxidant responses and metabolic pathways, in addition to cause damage at high concentrations. Physiological targets. Unlike ROS, aldehydes have a relatively long half-life. Thus, these compounds may not only react in the site where they are generated but may diffuse to distant sites in the cell and cause damage26, 27. At the same time, these compounds are considered important mediators of cell damage due to their ability to modify biomolecules in a covalent manner, which can interfere or regulate important cellular functions28. It has been shown that oxidative modification of proteins and their subsequent accumulation takes place in the cells during processes like aging, oxidative stress and several pathological conditions 26,

27

(Table 1). 12


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Aldehydes can react, non-enzymatically, mainly with the Cys sulfhydryl group, the -amino group of lysine and the imidazole group of histidine in proteins, by a Michael addition or the formation of a Schiff base 28-31. In this regard, there are 406, 500 Cys residues in protein entries in the GenBank protein file, with about 1.9 entries per gene. Thus, there are about 214, 000 unique Cys residues encoded in the human genome. Cys residues vary in their potential for oxidation depending on their accessibility within protein structures. However, a high percentage of Cys residues are part of active sites in enzymes, transporters, receptors, or transcription factors, which makes evident that there is a large number of redoxsensitive thiols within the Cys proteome14. Signaling pathways. Acrolein and 4-HNE are able to regulate many transcription factors, being the most important the nuclear factor-B (NF-B) and Nrf2 that regulate the expression of more than 400 genes involved in oxidative stress, apoptosis, inflammatory and immunological responses32,

33.

These transcription

factors contain several reactive Cys that act as oxidative stress sensors, but their presence also turns them more sensitive to oxidative damage 34.

Under basal

conditions, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap 1) in the cytosol.

This complex directs Nrf2 polyubiquitination and degradation.

During

oxidative stress, Nrf2 is liberated from Keap 1 and enters the nucleus to induce the expression of antioxidant response element (ARE)-containing genes35. 4-HNE has an important role in this pathway since it acts as a signaling molecule which stimulates the antioxidant defense network.

Specific Cys residues 13



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(Cys273/Cys288) in Keap 1 are known to act as sensors for oxidative stress, and their modification leads to a conformational change in Keap 1, with the consequent release of Nrf236. 4-HNE induces a conformational change in Keap 1 directly via adduct formation or indirectly by increasing the production of mitochondrial ROS, since it has been observed that 4-HNE can form adducts with complexes I, II and III of the respiratory chain, interfering with the proper flow of electrons, thereby resulting in high superoxide anion production and finally promoting mitochondrial dysfunction37-39. For this reason, the maintenance of the redox balance in the cell is important and one way to attain this is by regulating the concentration of aldehydes (Fig. 3). Metabolism.

Regardless

their

toxicity,

many

aldehydes

generated

from

lipoperoxidation can be successfully metabolized to less toxic compounds. In the cell there are different mechanisms to regulate the concentration of these aldehydes through the action of phase I and phase II metabolic mechanisms. The enzymes

involved

in

Phase

I

metabolism

of

aldehydes

are

aldehyde

dehydrogenases (ALDHs) and cytochromes p45040 that generate carboxylic acids by oxidation reactions, and aldo-keto reductases (AKR) or alcohol dehydrogenase (ADH), that generate alcohols through reduction reactions41,42.

Phase II

metabolism of reactive aldehydes is carried out by enzymatic glutathionylation by glutathione-S- transferases (GSTs), and the product of this last reaction can still be detoxified by ALDHs or AKRs, where ALDHs play the main role23, 42.

14


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ALDHs kinetic reaction mechanism. ALDHs super family is a highly conserved group of enzymes that catalyze the oxidation of a wide variety of aldehydes to carboxylic acids which are less toxic and more soluble20,

43.

The expression of

these enzymes is tissue specific and significantly increases in several diseases that involve the generation of oxidative stress44-46. The oxidation of aldehydes by these enzymes is NAD(P)+ dependent. In general, the kinetic mechanism of these enzymes is Bi Bi ordered (Fig. 4)47,

48.

The NAD(P)+ binding in the first step

decreases the pKa of the catalytic Cys located in the aldehyde binding site (Cys302 in ALDH2), allowing the proton abstraction from the sulfhydryl by a OHion generated by the deprotonation of a H2O molecule by the general base, an adjacent glutamate residue (E268 in ALDH2). Then, a nucleophilic reaction of the thiolate of Cys302 with the aldehyde takes place, resulting in the formation of a tiohemiacetal intermediary, followed by a hydride transfer to NAD(P)+, to form NAD(P)H and a thioester intermediary. After that, the thioester intermediary is hydrolyzed to a carboxylic acid, the first product of the reaction, by a H2O molecule which is also activated by the extraction of a proton by the general base. Finally, the reduced coenzyme is released from the catalytic pocket to regenerate the free enzyme and start a new catalytic cycle48, 49 (Fig. 4).

NAD+

E-SH

RCHO

H+ k1

E-S-

NAD+

O-

k3

O k5

E-S-C-R

NAD+ H

RCOO-

H2O

E-S-C-R NADH

k7

E-SH

NADH k9

E-SH

NADH

15



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Figure 4. General kinetic mechanism of aldehydes oxidation by ALDHs. The rate constants for the steps involved in the catalysis are k1, binding of oxidized coenzyme; k3, aldehyde binding; k5, hydride transfer; k7, deacylation; k9, release of the reduced coenzyme.

Participation of some ALDHs in the oxidative stress response and several related pathologies. ALDH1A1 Cataract formation. ALDH1A1 is a tetrameric cytosolic enzyme ubiquitously distributed in several tissues including: liver, kidney, lung, brain, eyes, testes and red cells50-55, where is crucial for the detoxification or regulation of the concentration of different aldehydes. In the eye, ultra violet radiation (UVR) is the most important environmental stress, because it continuously induces ROS production, generating lipid peroxidation, and producing aldehydes such as 4-HNE and

malondialdehyde

that

cause

protein

cross-linking,

denaturation

and

aggregation. In the cornea and the lens, ALDH1A1 is naturally over-expressed playing an important role in the detoxification of lipid aldehydes; the accumulation of these aldehydes increases the risk of cataract formation in mammals56, 57. Cancer. ALDH1A1 also exhibits high catalytic activity with the anti-cancer drugs oxazaphosphorines58

or

aldophosphamide,

carboxyphosphamide, a nontoxic metabolite59.

converting

this

compound

to

In assays with MDA-MB-468 16


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human breast cancer cells, the silencing of the ALDH1A1 gene increases the sensitivity to paclitaxel (taxol), which in turn decreases cell proliferation and increases caspase activity and the formation of ROS60.

Similar results are

obtained with doxorubicin, sorafenib and staurosporine. The opposite effect is observed when ALDH1A1 is present, indicating that this enzyme can decrease, indirectly, ROS production induced by anti-cancer agents, promoting the resistance of cancer cells to this kind of drugs60.

It has been

proposed that cancer cells acquire drug resistance by inducing ALDH1A1 expression61.

Indeed, increased ALDH1A1 expression in relapsing tumors of

human breast cancer after surgery and tamoxifen treatment has been observed62. Tamoxifen was recently reported as a nonessential mixed-type activator for ALDH1A1, increasing its activity by 60-80%63, which might help to explain the resistance of tumor cells to oxidative stress during treatment with this drug. ALDH1A1 expression in breast cancer has also been associated with advanced disease stages, triple negative cells and poor prognosis64. This isoform is currently used as a biomarker of pluripotency in breast epithelial cancers, since it is absent in normal breast tissue. ALDH1A1 gene is regulated directly by c-Myc, a transcriptional factor that regulates numerous genes involved in signal transduction in different kinds of cancer65. This enzyme is also inhibited by acetylation of lysine 353 (K353); in particular, acetyltransferase P300/CBP–associated factor (PCAF) and deacetylase sirtuin 2 (SIRT2) regulate the acetylation state of ALDH1A1-K353. Neurogenic 17



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locus notch homolog protein (NOTCH) may also activate ALDH1A1 through the induction of deacetylase sirtuin 2 (SIRT2), leading to ALDH1A1 deacetylation and enzyme activation, thereby promoting breast cancer stem cell self-renewal and tumor growth66. Neurodifferentiation and neuropathologies. In human brain, ALDH1A1 is highly expressed in dopaminergic neurons. In these neurons, the ALDH1A1 expression is under control of Pituitary homeobox 3 (Pitx3), a transcriptional factor that regulates the specificity and maintenance of different populations of dopaminergic neurons. During early development, retinoic acid is synthesized in dopaminergic neurons by ALDH1A1 and administration of retinoic acid can compensate for low ALDH1A1 expression as a consequence of Pitx3-deficiency. These observations indicate that ALDH1A1 seems linked to the differentiation and survival of specific dopaminergic neuronal subpopulations67. In the central nervous system (CNS), monoamine oxidase metabolizes dopamine to 3, 4- dihydroxyphenylacetaldehyde (DOPAL). DOPAL can be neurotoxic and its accumulation may lead to cell death associated with neurological disorders such as Parkinson´s disease (PD) due to the promotion of -synuclein polymerization68. ALDH1A1 plays a critical role in maintaining low levels of DOPAL by catalyzing the oxidation of DOPAL to 3, 4-dihydroxyphenylacetic acid (DOPAC), inhibiting the accumulation

of

neurodegeneration68,

cytotoxic 69.

-synuclein

aggregates

and

avoiding

However, Aldh1a1 knockout mice did not develop

dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc), 18


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although ALDH1A1 over expression in midbrain cultures from transgenic alphasynuclein mice protected the dopaminergic neurons70. Moreover, double knockout mice (Aldh1a1(-/-)/Aldh2(-/-)) developed age-related SNpc dopaminergic neuron loss. These results suggest that ALDH1A1 has a protective function for human dopaminergic neurons in the SNpc and the existence of a compensatory mechanism of ALDHs to maintain cell survival70. It has also been observed that the level of ALDH1A1 expression is high in mesencephalic neurons, whereas its mRNA levels are lower in patients with Parkinson disease71-73. Low ALDH1A1 levels are also found in postmortem human brains from patients with schizophrenia, which may be related to the etiology of the disease74. Retinoids metabolism. In liver, ALDH1A1 catalyzes the irreversible oxidation of retinal to retinoic acid (RA), the bioactive form of retinol. While the light absorption properties of retinaldehyde are a necessary element for vision, the all-trans and 9cis-RA isomers are ligands for two families of nuclear retinoid receptors, the retinoic receptor A and the retinoid receptor X, which are mediators of gene expression during growth and development75. RA may exert several physiological functions through the interaction with these receptors. Retinoids are involved in the pathogenesis of cancer, obesity, diabetes and cardiovascular diseases, where the metabolism of these compounds is strictly regulated by the activity of the ALDH1 family, specifically isoforms A1-A3. In this regard, a close relationship between vitamin A and its metabolites in glucose homeostasis, insulin sensitivity and adipogenesis has been established76, 77.

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In mice, liver deficiency of ALDH1A1 decreases the expression of key gluconeogenic

mediators

such

as

glucose

6

phosphatase

and

phosphoenolpyruvate carboxykinase, which appears to result from decreased RA levels and altered activation of the RAR / RXR receptors. ALDH1A1 deficiency also exerts a coordinated dual effect that involves increasing fatty acid oxidation and decreasing circulating triacyl glycerides (TAG) levels78. On the contrary, the aberrant expression of ALDH1A1 has been associated with the T cell acute lymphoblastic leukemia (T-ALL), due to excessive RA generation as a metabolic product of this enzyme, which promotes an unregulated growth within the thymus and promotes malignancy79. RA elimination involves its oxidation to 4-hydroxyand 4-oxo-retinoic acids by cytochrome P450 26 (CYP26), and these compounds are subsequently conjugated by UDP-glucoronyl transferases for excretion in the bile80.

ALDH2 Alcohol metabolism and cancer. ALDH2 is a mitochondrial matrix enzyme that has high affinity for acetaldehyde, an intermediary of ethanol metabolism and plays an important role in the detoxification of this toxic metabolite generated after ethanol ingestion. Almost half of the Eastern Asian population (40%) is very susceptible to alcohol consumption and this phenotype has been associated with a genetic ALDH2 deficiency, due to a polymorphism named ALDH2*281, 82, that involves the replacement of a glutamate residue by lysine in position 487, ALDH2(E487K). 20


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This amino acid change prevents the formation of two important H-bonds, destabilizing the structure mainly at the NAD+ binding site region, drastically diminishing the affinity for this coenzyme83 and activity by about 90%5,

84.

The

presence of this polymorphism increases the risk for the development of different types of cancer, since acetaldehyde reacts with cellular proteins and DNA forming adducts, that lead to DNA damage and organ injury

85.

Also, the E487K change

increases the ALDH2 protein turnover rate, leading to loss in total ALDH2 protein86, 87.

Therefore, the stabilization and protection of this enzyme seems physiologically

relevant. For instance, it has been observed that in umbilical cord cells (HUVEC), transfected with the ALDH2 gene and exposed to different concentrations of acetaldehyde, the aldehyde levels are lower and as a consequence, also the generation of ROS, apoptosis and activation of stress marker molecules, such as extracellular signal-regulated kinases (ERK1/2), as well as decreased p38 MAP kinase. These data highlight the therapeutic potential of ALDH2 in the prevention of cell damage induced by ethanol consumption88. Neurodegeneration.

The

molecular

basis

of

pathogenesis

for

most

neurodegenerative disorders are not completely elucidated, although mitochondrial dysfunction, inflammation, cytotoxicity, elevated oxidative stress, toxicity by aldehydes and environmental factors play important roles 89.

Mitochondrial

dysfunction and the subsequent oxidative stress promote the generation of ROS. These processes contribute to neurodegeneration via lipid peroxidation, which consequently leads to the production of reactive aldehydes, such as DOPAL, 3,4dihydroxyphenylglycolaldehyde (DOPEGAL), malondialdehyde (MDA), and 421



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HNE89-91. High incidence of Parkinson's disease has been associated with chronic exposure to different pesticides.

Fungicides such as maneb, mancozeb and

benomyl at 10 M do not affect mitochondrial respiration, but inhibit ALDH2 and ALDH5 activities92, and as these enzymes detoxify DOPAL, their inhibition may decrease the metabolism of this toxic aldehyde in the CNS93. A decreased ALDH2 activity promotes the accumulation of acetaldehyde and 4-HNE, which may be related with Alzheimer disease (AD) development. Mice with low ALDH2 activity show neurodegeneration in an age-dependent manner, accompanied by memory loss, highlighting the ALDH2 participation in these pathologies53, 94. AD is a neurodegenerative disorder usually associated with age, clinically characterized by a progressive loss of memory, due to a decline in neurofibrillary connections that generates synapses loss. In this disease, neurons are subjected to high levels of oxidative stress95, and further lipid peroxidation and protein oxidation, that promotes neurodegeneration. The -amyloid peptide (A) is formed by 39-43 amino acids located in the center of senile plaques (SP) and has been described as causal agent of lipid peroxidation, because it alters the fluidity of neuronal membranes in the brain, affecting the activity of various proteins including ion channels, which probably induces mitochondrial dysfunction. These Aeffects can be inhibited by anti-oxidant agents such as Trolox (an analogue of vitamin E)9699.

-amyloid peptide (A1-42) acquires a helical structure. It has been proposed that the carbonyl oxygen atom of isoleucine residue (Ile-31) interacts with S-atom of 22


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methionine residue 35 (Met-35) generating sulfuranyl, a transient free radical that is able to extract an allylic H-atom from the acyl chain of a phospholipid in the membrane forming a lipid radical, which reacts with O2 to generate a lipid peroxyl free radical (ROO·), that is critical to trigger oxidative stress, lipoperoxidation and neurotoxicity100,

101.

This last process induces the generation of 4-HNE and

acrolein99, 102, which alter the conformation of different membrane proteins and are toxic to neurons29, 99, 103, 104. The concentration of 4-HNE is elevated in multiple regions of the brain and cerebrospinal fluid in AD105, also elevating the protein-HNE adducts106. It has been observed that 4-HNE is neurotoxic to hippocampal neurons of rats, possibly by altering the homeostasis of Ca2+, lowering the Na+/K+-ATPase activity99 and impairing glucose transport107. High levels of expression and activity of ALDH2 in cerebral cortex, hippocampus (glia and senile plaques), basal ganglia, cerebellum and midbrain have been found in this disease. Similarly, the ALDH2 activity was significantly increased in temporal cortex of AD patients, unlike control subjects, suggesting that ALDH2 is one of the mechanisms of detoxification and protection in the cerebral cortex in AD53. The 4-HNE concentration in postmortem analysis of ventricular fluid from AD individuals was significantly higher (15-120 M) than that obtained from aged control individuals (8.6 M)108. These observations correlate with reports showing that inhibition of Complex I of the respiratory chain modified the NAD+ availability which diminished the activity of ALDH and decreased 4-HNE metabolism by brain 23



Page 24 of 57

mitochondria23. Furthermore, ALDH2 activation by ALDA-1 prevents -amyloidinduced endothelial cell dysfunction and restores angiogenesis and mitochondrial function in the endothelium. Thus, activating agents of ALDH2 (see section below) may attenuate endothelium damage including that occurring in cerebral amyloid angiopathy, preserving the angiogenic potential of the endothelium109. Angiogenesis. It has been shown that ALDH2 may also regulate angiogenesis probably through hypoxia-inducible factor 1HIF-1and vascular endothelial growth factor (VEGF).

In a mice ischemia-reperfusion model, the ALDH2-

knockdown impaired angiogenesis, causing diminished perfusion recovery and small artery and capillary density, and increased muscle atrophy, while the overexpression of ALDH2 restored the angiogenesis process. In addition, patients with ALDH2-deficient genotype show a higher risk of developing poor coronary collateral circulation. Thus, the ALDH2 deficiency deteriorates the endothelial cell function and HIF1/VEGF signaling cascade, since there is a direct correlation between the expression of ALDH2 and HIF-1/VEGF under hypoxia. When ALDH2 is overexpressed increased HIF-1 and VEGF levels are observed and the opposite effect is attained when ALDH2 is down regulated; however, the detailed mechanisms underlying these processes have not been fully elucidated110. Myocardial damage. ALDH2 has also been identified as an enzyme whose activation correlates with a decrease in myocardial damage in ischemic heart. In a rodent model, when a specific activator of ALDH2 (ALDA-1) is administered 24


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previously to the ischemic event, the infarct size decreases by 60%.

The

byproduct of lipid peroxidation 4-HNE, is the most abundant compound that accumulates during an ischemic cardiac event and the elimination of this toxic aldehyde by ALDH2 may be one of the mechanisms by which this enzyme protects the heart against ischemic damage44, 11. ALDH2 catalyzes the release of nitric oxide (NO) from nitroglycerin to achieve vasodilatation in angina pectoris, myocardial infarction and heart failure. However, patients develop nitroglycerin tolerance after a prolonged treatment.

This last

effect can be explained by the NO inactivation of ALDH2, by interacting with critical amino acids at the active site.

Since nitroglycerin inactivation of ALDH2 is

completely prevented by the reducing agent dithiothreitol, it has been suggested that the mechanism of inactivation is related to the oxidation of Cys residues located in the catalytic tunnel of ALDH2 forming SNO, affecting its catalytic function and promoting the increment of toxic aldehydic protein adducts and oxidative stress levels in the organism112. Fructose metabolism and NASH. During the oxidative stress generated by chronic hyperglycemia the ALDH2 activity is compromised, which may be involved in left ventricular dysfunction in diabetic hearts113. derivatives

glyceraldehyde

and

Diets high in fructose or in its

glycolaldehyde

can

induce

non-alcoholic

steatohepatitis (NASH) in rats and this disease has been associated with increased oxidative stress markers114. These sugar metabolites can be oxidized by ROS to form the highly toxic or genotoxic dialdehyde glyoxal.

In hepatocytes, 25



Page 26 of 57

glyceraldehyde, glycolaldehyde and glyoxal are eliminated by ALDH2 and its inhibition increases the toxicity of these aldehydes, as well as the content of carbonylated proteins, demonstrating the importance of ALDH2 in non-alcoholic steatohepatitis46. Muscle atrophy. It was recently showed that exhaustive exercise diminishes ALDH2 activity, which increases the 4-HNE-protein adducts in skeletal muscle and decreases the levels of mitochondria-specific MnSOD and phase 2 enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO-1). In contrast, the over-expression of ALDH2 in skeletal muscle restores the imbalance between prooxidant and antioxidant components attenuating oxidative stress, but favoring muscle atrophy and decreasing endurance capacity. ALDH2 over-expression also decreases the expression of Bcl-2 nineteen-kilodalton interacting protein 3 (Bnip3) and LC3phosphatidylethanolamine conjugate (LC3II), which are linked to mitophagy, and suggesting a strong participation of ALDH2 in the Bnip pathway115.

26


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ALDH3A1 ALDH3 family is constituted by enzymes that oxidize medium-chain aliphatic and aromatic aldehydes.

High activity of ALDH3A1 has been found in cornea,

stomach, liver, urinary tract and some types of cancer116. Cell cycle. ALDH3A1 has the ability to regulate cell proliferation and, since it is present in both the nucleus and cytosol, it can regulate the cell cycle117. It has been observed that cell lines that express high levels of ALDH3A1 are more resistant

to

the

antiproliferative

effects

of

aldehydes

derived

from

lipoperoxidation118, whereas ALDH3A1 inhibition by antisense oligonucleotides decreases cell growth, due to the accumulation of MDA and 4-HNE119. Constitutive expression of ALDH3A1 in rat hepatoma cells favors cell growth by detoxifying aldehyde products of lipid peroxidation118. There is evidence that the expression of ALDH3A1 is down regulated by PPAR (Peroxisome Proliferator-Activated Receptor Gamma) and ALDH3A1 expression directly correlates with cell proliferation.

Then, it seems that by modulating

PPARmediated ALDH3A1 expression it would be possible to deter the accelerated cell proliferation of tumors cells or stimulate cell proliferation in normal cells during tissue regeneration120. In in vitro experiments, it has been observed that ALDH3A1 can decrease DNA damage and apoptosis promoted by several toxic compounds including hydrogen peroxide, mitomycin C and etoposide, through modulation of cell cycle to facilitate DNA repair121.

27



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Although the mechanisms by which ALDH3A1 can influence cell proliferation have not been fully clarified, they may include the modulation of genes involved in transcriptional

regulation,

cell

growth,

differentiation,

apoptosis

and

lipid

peroxidation. For example, ALDH3A1 is highly expressed in cells obtained from lung cancer (NSCLC)122 patients.

In these cells, proliferation is significantly

affected when the ALDH3A1 activity is lowered by siRNA, probably due to the ability of this enzyme to affect a broad spectrum of genes that have important roles in the cell. These genes include CCL20, GPR37, DDX3Y, ID4, GPC6, RPS4Y1, EIF1AY and HMGA2, which are involved in transcriptional regulation, cell growth, differentiation and apoptosis123-125. Cancer. ALDH3A1 also has an important role in the metabolism of aldehydes derived from lipid peroxidation, such as alkanals and alkenals of medium chain, and 4-hydroxyalkenals. ALDH3A1 expression turns normal and tumor cells more resistant to the effect of lipid peroxidation products126. The human lung tumor cells A549 express high levels of ALDH3A1, and this cell line is less susceptible to the antiproliferative effects of 4-HNE, compared with human hepatoma HepG2 or SKHEP-1 cells, which show a lower ALDH3A1 expression. In contrast, the increased PPAR level in the A549 cell line promotes a diminution in ALDH3A1 mRNA, protein levels, and activity, which makes these cells more susceptible to lipid peroxidation products127.

These data clearly establish an inverse relationship

between PPAR and ALDH3A1.

28


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ALDH3A1 expression is differentially affected by hormones such as progesterone and cortisone, suggesting a potential hormones-dependent role in some tumors 128. In addition, ALDH3A1 expression is also induced by several xenobiotics, including polycyclic hydrocarbons (PAHs) and 3-metylcolantrene, through multiple response elements to xenobiotics (XREs)129,

130.

These data suggest that ALDH3A1 is an

important regulatory element in cell stress defense. Eye protection against UV light. ALDH3A1 constitutes 20-40% of total soluble proteins in human cornea122, 131, and it has been proposed that this enzyme plays multiple essential roles in this organ, such as metabolism of toxic aldehydes, direct absorption of UV light, antioxidant function either directly through the scavenging of free radicals or indirectly by the production of NADPH, maintaining (i) corneal refractivity and transparency properties as a corneal crystalline, (ii) chaperon-like activity, and (iii) cell cycle regulation132-136.

The protective effect of ALDH3A1

against the presence of 4-HNE is demonstrated in transfected cells of cornea lacking the endogenous expression of this enzyme. Transfected cells are more resistant to apoptosis induced by 4-HNE than non-transfected cells with the ALDH3A1 gene. The ALDH3A1 over-expression also prevents the formation of adducts with proteins in cornea137. Sjögren-Larsson syndrome. The ALDH3A2 (FALDH) gene is located in chromosome 17p11.2, spans 31 kb in size and is involved in the metabolism of lipids138,

139.

ALDH3A2 oxidizes aliphatic aldehydes (C6-C24) to fatty acids,

including monounsaturated, polyunsaturated and methyl-branched aldehydes140. 29



Page 30 of 57

Deficiency or polymorphisms in ALDH3A2 have been related with Sjögren-Larsson syndrome, a rare neurocutaneous disease derived from an autosomal recessive disorder characterized by ichthyosis, mental retardation and spastic diplegia. In this syndrome the oxidation of fatty aldehydes is impaired leading to accumulation of lipid aldehydes141.

Although ALDH3A2 is a housekeeping protein that is

constitutively expressed in all tissues, some drugs and pathological conditions can induce its expression, and it can also be up-regulated by insulin and downregulated in diabetes142. There are more than 80 mutations in ALDH3A2 in patients with Sjögren-Larsson. These include missense mutations, small deletions and insertions, splicing site mutations and complex rearrangements.

These mutations lead to loss of

approximately 90% of the catalytic activity143. The potential disease mechanisms leading to symptoms include: (i) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; (ii) physical disruption of multi-lamellar membranes in skin and brain; (iii) abnormal activation of the JNK cell signaling pathway; and (iv) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression. Currently, no effective pathogenesis-based therapy is available for this disease144, although the modulation of the expression and activity of this enzyme appears to be very important to contend with the ethyology of this pathology.

30


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ALDH5A1/SSADH One source of aldehydes generation in the CNS is the enzymatic oxidative deamination of amine neurotransmitters such as GABA and dopamine, leading to the generation of succinic semialdehyde (SSA) and DOPAL, respectively145. SSA is oxidized to succinic acid by the succinic semialdehyde dehydrogenase (SSADH/ALDH5A1); this enzyme is located in the mitochondrial matrix and has high selectivity for SSA146. Neuronal disorders. Genetic SSADH deficiency is inherited in an autosomal recessive fashion, caused by mutations in the ALDH5A1 gene in chromosome 6p22.3. In humans, it leads to severe neurodevelopmental abnormalities, due to excessive concentrations of -hydroxybutyrate (GHB), the biochemical hallmark of this disorder that is excreted in the urine147,

148.

Furthermore, in cerebral cortex

and hippocampus from patients with AD a succinic semialdehyde reductase (AKR7A2) has been located. This enzyme catalyzes the conversion of SSA to GHB and has been proposed that this enzyme plays a dual role in the cytoprotection and neuromodulation of CNS; however, this has not been completely elucidated149. GABA is generated from glutamate by glutamate decarboxylase and metabolized to succinate in the mitochondrial matrix by the successive action of GABA transaminase and SSADH. In the absence of SSADH, GABA is not transformed to succinic acid, but is converted to -hydroxybutyric acid and accumulation of GHB causes γ-hydroxybutyric aciduria. GHB at 100 M produces hyperporalization of 31



Page 32 of 57

the cell membrane150 and alters dopamine levels, which activates tyrosine hydroxylase151.

Nowadays, more than 176 cases of this pathology have been

reported worldwide152. The main neurological symptoms include language delay, ataxia, hypotonia and mental retardation. Some patients show loss of short term memory, behavior disorders such as signs of autism, hallucinations and hostile or aggressive behavior. In critical cases seizures, choreoathetosis, myoclonus and optic atrophy are observed, which can lead to premature death153. ALDH5A1-deficient mice also show increased concentrations of GABA, which increase mitochondria number and induce oxidative stress.

In addition,

metabolites associated with GABA metabolism (-hydroxybutyrate, succinic semialdehyde, D-2-hydroxyglutarate, 4, 5-dihydrohexanoate) and oxidative stress significantly increase in multiple tissues of aldh5A1-/- mice154, 155. These metabolic perturbations are associated with decreased levels of GSH in brain, as well as increased levels of adducts of the lipid peroxidation by-product 4-HNE; since ALDH5A1 is the predominant enzyme for HNE oxidation in this organ; however, its participation in the detoxification of this metabolite in the liver is marginal156.

32


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Modulators of ALDHs Due

to

the

essential

and

crucial

participation

of

ALDHs

in

several

physiopathological processes, the study and design of compounds and strategies to modulate the activity of these enzymes takes clinical and pharmacological relevance. Recently, several compounds have been reported as modulators of ALDHs, particularly a family of compounds with a core structure of 3-amino-1phenylpropan-1-one, called Aldi-1, Aldi-2, Aldi-3 and Aldi-4 (Fig. 5).

These

molecules behave as inhibitors of ALDH1A1, ALDH2 and ALDH3A1 with IC50 values of 1-12 M157.

33



Page 34 of 57

Figure 5. Structure of some modulators of aldehyde dehydrogenases. A, new generation of inhibitors of ALDHs; B, reported activators of ALDHs. Preparation of the figure was accomplished as indicated in the legend to Fig. 1.

To date, only few ALDHs activators (Fig. 5) have been reported. For instance, Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide) and Alda-89 (5-(2propenil)-1,3-benzodioxol) behave as moderate human ALDH2 and ALDH3A1 activators, respectively44,

158.

Tamoxifen (Fig. 5) was recently reported as an

activator of human ALDH1A163. Alda-1 is a non-essential activator of ALDH2 and has been proposed as a molecular chaperone, since it restructures the inactive tetramer of ALDH2*2, enhancing the affinity for NAD+ and restoring activity.

According to the 34


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crystallographic structure, this compound binds to the entrance of the aldehyde binding site modifying the environment of the catalytic pocket159. The effects of the Alda-1 binding to the enzyme include the diminution of the catalytic Cys pKa by about 1 pH unit, favoring the nucleophilicity and reactivity of this residue. Further, the Alda-1 binding to ALDH2 modifies the order of substrates entry and products release, modifying the kinetic properties of the enzyme160.

The activation

mechanism by Alda-1 ultimately resides on the acceleration of the deacylation rate, the limiting step of the reaction160.

Alda-1 also improves the enzyme stability,

protecting it from inactivation by lipid aldehydes161. In addition Alda-1 activates human ALDH1A1160, and this observation may allow to broaden its use to different tissues160. Due to its mitochondrial localization, ALDH2 has been proposed as a therapeutic target to diminish oxidative stress. In consequence, the effect of ALDH2 activation has been evaluated in several models that mimic different pathologies, such as neurodegenerative processes162, pulmonary arterial hypertension163, depression164, hepatic damage165, among others. ALDH2 has also been implicated in the regulation of nociception and proposed to serve as a molecular target for pain control, as in a model of ALDH2*1/*2 mice the nociceptive behavior increases as compared with the wild-type mice166. Administration of Alda-1 in rats also increases the nociceptive threshold to thermal and mechanical stimulation166. Despite the therapeutic potential of Alda-1, there are not current reports of clinical trials for this compound. 35



Page 36 of 57

Regarding Alda-89, the mechanism by which this compound activates ALDH3A1 is still unknown. However, this compound has been used in adult human and murine submandibular gland stem cells to assess the role of ALDH3A1 on the growth of head and neck cancer and on the preservation of the salivary function after radiation treatment. ALDH3A1 activation of 304% by 50 M Alda-89, using 2.5 mM NAD+ and 10 mM acetaldehyde as substrates has been reported158,

167.

has no effect on the ALDH1A1, ALDH2 and ALDH5A1 activities158.

Alda-89 Alda-89

(safrole) is a natural constituent of a number of spices such as nutmeg, mace, cinnamon, anise, black pepper and sweet basil and is used in food and beverages as flavoring. However, this compound has been classified by IARC as possibly carcinogenic for humans (group 2B), since it has resulted to be carcinogenic in animal studies and genotoxic in vitro168. Therefore, extreme caution should be observed for its use in humans. Tamoxifen is currently used as a selective estrogen receptor modulator in patients with ER positive breast tumors169.

This anti-cancer pro-drug is also a

nonessential mixed-type ALDH1A1 activator, modifying the Km for substrates and increasing Vmax by about 2-fold63. Tamoxifen (15 M) increases (5-fold) the IC50 of ALDH1A1 for daidzine, indicating that tamoxifen and daidzine compete for the aldehyde binding site. The activation mechanism of ALDH1A1 by tamoxifen relies on the acceleration of the reduced coenzyme release, which is rate limiting for this enzyme63. Tamoxifen also confers structural stability to the protein, protecting it from thermal denaturation. These data suggest that tamoxifen could be used as 36


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an activator as well as a stabilizer of ALDH1A1, facilitating the detoxification of aldehydes and decreasing the damage that the accumulation of these toxic compounds can generate63. Nevertheless, caution should be also observed for its use in humans since patients with breast cancer develop resistance to the tamoxifen treatment after two years. None of the aforementioned compounds have been clinically tested for their effect as ALDH activators. Then, it is important to continue with the search and design of molecules able to activate ALDHs and/or protect these enzymes from inactivation, in order to be able to successfully use them in the clinic to contend with oxidative stress in different pathologies.

Conclusion ALDHs participate in the detoxification of the lipid peroxidation byproducts. Thus, the contribution of these enzymes to the protection of the cell from lipid aldehydes in conditions that involve high levels of oxidative stress, make them essential factors for cell survival. Several reports have shown that the use of activators of these enzymes mitigates the effects of oxidative stress in different models of pathologies. These enzymes are involved in different signaling pathways, where the regulation of the aldehydes concentration is crucial for cell growth and development, as well as physiopathological processes such as cell differentiation, neurotransmission, inflammatory pain, cardiovascular events, carcinogenesis. Therefore, ALDHs have become interesting and promising therapeutic targets for 37



Page 38 of 57

the treatment of different pathologies, and hence identifying and designing new molecules to modulate their activity is emerging as a pharmacological attractive task.

Acknowledgements. This work was supported in part by CONACyT-México grants Nos. 166463 and 257943. The authors declare no competing financial interest.

Abbreviations: AD, Alzheimer´s disease; ALDHs, aldehyde dehydrogenases; ALDA-1, N-(1,3benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; ARE, antioxidant response element; CNS, central nervous system; DOPAL, 3-4-dihydroxyphenylacetaldehyde; DOPEGAL, 3-4-dihydroxyphenylglycolaldehyde; DOPAC, 3,4dihydroxyphenylacetic acid; EGFR, epidermal growth factor receptor; GABA, aminobutyric acid; GHB, -hydroxybutyrate; GSH, glutathione; 4-HHE, 4-hydroxy-2hexenal; 4-HNE, 4-hydroxy-2-nonenal; HUVEC, human umbilical vein endothelial cells; Keap-1, Kealch-like ECH-associated protein 1; LDL, low density lipoproteins; MDA, malondialdehyde; NF-B, nuclear factor-B; NO, Nitric oxide; NASH, Nonalcoholic steatohepatitis; NSCLC, Non-Small Cell Lung Cancer; PAHs, polycyclic hydrocarbons; PPAR, peroxisome proliferator activated receptor; PDGFRplatelet-derived growth factor receptor-; RA, retinoid acid; ROS, reactive oxygen species; SOD, superoxide dismutase; SIRT-1, carbonylation of deacetylase sirtuin 1; SIRT2, deacetylase sirtuin 2; SNpc, subtantia nigra pars compacta; SSA, succinic semialdehyde; SSADH, succinic semialdehyde dehydrogenase or ALDH5A1; XREs, xenobiotic response elements.

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Table 1. Principal sources of aldehydes.

Aldehydes acetaldehyde

acrolein

4-hydroxy-2nonenal

Sources Ethanol metabolism in the liver

Exogenous: cooking or frying foods, beer and other alcoholic beverages. Industrial applications, incomplete combustion, smog and cigarette smoke. As contaminant in air or water (US EPA) Endogenous: Lipoperoxidation Produced at inflammatory sites from L-serine and L-threonine. Lipoperoxidation

Consequences 1) Carcinogen Group 1 by IARC 2) Adducts with amino group of deoxyguanosine. 3) Related with carcinogenesis of squamous epithelium of the esophagus, head and neck (HNSCC). 4) Allodynia 1) Inhalation can generate cardiovascular disorders. 2) Increases ROS and depletes pools of glutathione. 3) Induces neurodegeneration of the nigrostriatal dopaminergic system. 4) Induces programmed cell death through caspase 3 pathway and other kinases such as RIPK-I and RIPK-3. 5) Low concentrations = apoptosis 6) High concentrations = necrosis 1) Regulates transcription factors such as NFB and Nrf2. 2) Adducts with complexes I, II and III of the respiratory chain and with F1F0-ATP synthase, disrupting ATP synthesis and promoting cell damage. 3) High levels of ROS. 4) Decrease the rate of glucose transport in endothelial cells. 5) Upregulates the activity or expression of p38, ERK/AP-1 and COX-2 in YPEN-1 cells. ACS Paragon Plus Environment

References 170,171

166 16-19 172-174 175 176

177-179 32,33 37-39

180 181 55

182

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

DOPAL

CNS

6) Induces COX-2 expression via p38 MAPK pathway. 7) Activates PI3K/Akt signaling cascade that controls metabolic functions, survival pathways and mitogenic response. 8) Allodynia 9) Carbonylation of SIRT-1 impairing liver kinase B1/AMP activated protein kinase (LKBIAMPK) and exacerbates myocardial ischemia-reperfusion injury. 10) HNE-Lys and HNE-His adducts have been detected in human aortas in atherosclerotic areas related with aging 1) Accumulation is associated with neurological disorders such as Parkinson´s disease

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183

184, 185 166 186

27

68

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Table 2. Physiological roles proposed for ALDHs

ALDH isoform ALDH1A1

ALDH2

ALDH3A1 ALDH5A1

Function and pathologies related Detoxification of lipid aldehydes produced by UV light in cornea and lens. Detoxification of drugs used against cancer such as aldophosphamide and oxaphosphorines. Oxidation of retinal to retinoic acid. Converts DOPAL to DOPAC reducing his neurotoxicity in CNS. Aberrant expression associated with T cell acute lymphoblastic leukemia. Acetaldehyde metabolism. ALDH2*2 polymorphism increases the risk to develop different types of cancer. Activation correlates with a decrease in myocardial damage in ischemic heart. Metabolism of nitroglycerin in treatment of angina pectoris. NASH Protects against UV-induced oxidative stress. Polymorphisms in ALDH3A2 are related with Sjögren-Larsson syndrome. Genetic deficiency leads to severe neurodevelopmental abnormalities.

References 56, 57 58, 59 67, 75 68 79 85

44, 111 112 46 122, 131 143 147, 148

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Role of aldehyde dehydrogenases in physiopathological processes

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