DNA damage induced by endogenous aldehydes: Current state of knowledge

Mutation Research 711 (2011) 13–27

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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres

Review

DNA damage induced by endogenous aldehydes: Current state of knowledge Georgia-Persephoni Voulgaridou a , Ioannis Anestopoulos a , Rodrigo Franco b , Mihalis I. Panayiotidis c,d , Aglaia Pappa a,∗ a

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, 68100, Greece Redox Biology Center & School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA c School of Community Health Sciences, University of Nevada, Reno, NV 89557, USA d Department of Pathology, Medical School, University of Ioannina, University Campus, Ioannina 45110, Greece b

a r t i c l e

i n f o

Article history: Received 23 November 2010 Received in revised form 1 March 2011 Accepted 3 March 2011 Available online 16 March 2011 Keywords: Aldehydes Oxidative stress DNA damage 4-Hydroxy-2-nonenal (4-HNE) Acrolein Malondialdehyde (MDA) Crotonaldehyde (Cr) 4-Oxo-trans-2-nonenal (4-ONE) Formaldehyde (FA) Methylglyoxal (MG) Glyoxal Acetaldehyde (AA) Glyceraldehyde (GA)

a b s t r a c t DNA damage plays a major role in various pathophysiological conditions including carcinogenesis, aging, inflammation, diabetes and neurodegenerative diseases. Oxidative stress and cell processes such as lipid peroxidation and glycation induce the formation of highly reactive endogenous aldehydes that react directly with DNA, form aldehyde-derived DNA adducts and lead to DNA damage. In occasion of persistent conditions that influence the formation and accumulation of aldehyde-derived DNA adducts the resulting unrepaired DNA damage causes deregulation of cell homeostasis and thus significantly contributes to disease phenotype. Some of the most highly reactive aldehydes produced endogenously are 4-hydroxy-2-nonenal, malondialdehyde, acrolein, crotonaldehyde and methylglyoxal. The mutagenic and carcinogenic effects associated with the elevated levels of these reactive aldehydes, especially, under conditions of stress, are attributed to their capability of causing directly modification of DNA bases or yielding promutagenic exocyclic adducts. In this review, we discuss the current knowledge on DNA damage induced by endogenously produced reactive aldehydes in relation to the pathophysiology of human diseases. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Types of aldehydes-induced DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. 4-Hydroxynonenal (4-HNE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Acrolein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Malondialdehyde (MDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Crotonaldehyde (Cro) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. 4-Oxo-2-nonenal (4-ONE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Formaldehyde (FA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Methylglyoxal (MG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Glyoxal (Gx) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9. Acetaldehyde (AA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10. Glyceraldehyde (GA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.11. Detection of aldehydes-induced DNA adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Dragana, 68100 Alexandroupolis, Greece. Tel./Fax: +30 2551030625. E-mail address: [email protected] (A. Pappa). 0027-5107/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2011.03.006

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction DNA damage plays a major role in mutagenesis, carcinogenesis, aging and various others pathophysiological conditions. DNA damage can be induced through hydrolysis, exposure to reactive oxygen species (ROS) and other reactive metabolites. The reactions often are activated by exposure to exogenous chemicals and environmental factors, but often result endogenously as a consequence of metabolic endogenous processes. Aldehydes are highly reactive molecules that are intermediary or final products of metabolism involved in a wide spectrum of biochemical, physiological and pharmacological processes. Endogenous aldehydes are produced during the metabolism of amino acids, carbohydrates, lipids, biogenic amines, vitamins and steroids. Also the biotransformation of a large number of environmental agents and drugs leads to the generation of aldehydes. Aldehydes, being highly reactive electrophilic molecules, interact with phospholipids, proteins and DNA while their mediated effects vary from physiological and homeostatic to cytotoxic, mutagenic or carcinogenic [1,2]. A major source of endogenously produced aldehydes is the lipid peroxidation process. During lipid peroxidation (LPO) a variety of reactive oxygen/nitrogen species (ROS/RNS) oxidize lipids leading to free radical chain reactions and subsequent formation of byproducts, like lipid radicals, hydrocarbons and aldehydes [3,4]. These products further react and modify both proteins and DNA resulting in toxicity or even mutagenesis and therefore have been associated with aging, cardiovascular diseases, neurological disorders and cancer [3,5]. Aldehydes are well-studied products of LPO, with the ␣,␤-unsaturated to be the most cytotoxic by reacting with phospholipids, proteins and DNA. However, their effects are not only toxic but rather homeostatic as they participate in signal transduction pathways [4,6,7]. There are multiple mechanisms for aldehydes formation during lipid peroxidation. One common mechanism begins with singlet oxygen and its reaction with unsaturated lipids, which produces hydrogen peroxide. Hydroperoxide reacts with the protein myeloperoxidase and leads to the formation of hypochlorous and hypobromous acid when chloride and bromide are present, respectively. The interaction of the acids with amines produces chloroamines and bromoamines and eventually aldehydes [3]. The major aldehyde products of LPO are 4-hydroxynonenal (4-HNE), acrolein, malondialdehyde (MDA) and crotonaldehyde (Cr). These are highly reactive molecules that damage DNA by the formation of exocyclic adducts most of which are anticipated to be highly mutagenic. MDA is considered to be the most mutagenic product of lipid peroxidation, whereas 4-HNE is the most toxic [8]. LPO, together with the glycation process often leads to the formation of reactive carbonyl species (RCS) which are potent mediators of cellular carbonyl stress [9]. Glycation is considered to be the major source of RCS such as glyoxal and methylglyoxal and together with oxidative stress are two important biochemical processes known to play a key role in complications of many disease states. Of the most biologically important carbonyl compounds are methylglyoxal (Mg) and glyoxal (Gx) which readily form DNA adducts generating potential promutagenic DNA lesions. In general, aldehydes can damage DNA either directly by reacting with DNA bases, by generating more reactive bifunctional intermediates, which form exocyclic DNA adducts or formation of ethenobases initiated by addition of an

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exocyclic aminogroup of a DNA base (reviewed in [10] (Scheme 1). Of these, 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), acrolein, and crotonaldehyde have been most intensely studied with respect to their chemical and biological interactions with nucleic acids. The ability of these reactive electrophiles to modify DNA bases, yielding promutagenic lesions, is considered to contribute to the mutagenic and carcinogenic effects associated with the elevated levels of endogenously produced reactive aldehydes under stress conditions. Herein, we present a review on the current knowledge of DNA adducts induced by endogenously produced aldehydes in relation to published adduct types and their significance in biology and pathophysiology of human diseases. 2. Types of aldehydes-induced DNA damage 2.1. 4-Hydroxynonenal (4-HNE) 4-HNE is a 9-carbon ␣,␤ unsaturated aldehyde (enal) formed when n-6 polyunsaturated fatty acids such as arachidonic and linoleic acid are attacked by peroxidative free radicals during LPO. 4-HNE is a highly chemically reactive molecule and is considered one of the major generators of oxidative stress, often used as a bioactive marker of the extent of oxidative stress and LPO in a variety of biological systems [11–13]. There are two different pathways that lead to 4-HNE production during LPO process, an enzymatic and a non-enzymatic one. While the enzymatic pathway for 4HNE production appears to be more prominent in microsomes [14] the non-enzymatic pathway is less understood involving dimerized and oligomerized fatty acids derivatives as key intermediates [15]. Following the non-enzymatic pathway, the autoxidation of linoleic acid leads to the formation of 9-and 13-hydroperoxides (9HPODE/13-HPODE), which further gives 3Z-nonenal. This is further non-enzymatically oxidized to give 4-HPNE [16]. The enzymatic pathway involves the enzymes lipoxygenase and hydroperoxide lyase. Briefly, linoleic acid is enzymatically cleaved to 3Z-nonenal, which subsequently oxygenates to 4-HPNE in a non-enzymatic way [15]. 4-HPNE is subsequently decomposed to 4-HNE or 4-oxononenal (4-ONE). Cells have many mechanisms to remove 4-HNE through several metabolic pathways with the most important one being the tripeptide glutathione (GSH). This reacts with 4-HNE (both enzymatically and non-enzymatically) to form a conjugate which can be a target for further enzymatic deactivation or cellular export by specific transporters (e.g. MRP2). The mitochondrial aldehyde dehydrogenase ALDH2, using NAD as a co-factor, also oxidizes 4HNE to 4-hydroxynonenal-2 enoic acid (4-HNA). Other enzymes that could use as a substance 4-HNE are aldehyde reductase, aldose reductase and aldo-keto reductase, which reduce 4-HNE to 1,4dihydroxy-2-nonene (DHN) in an NADPH-dependent manner [4]. 4-HNE capability to form protein adducts (through interactions with Cys, His and Lys residues) could lead to mitochondrial malfunctions and inhibition of cell signaling and is believed to be one of the reasons for the elevated levels of HNE in various diseases like Alzheimer, Parkinson and arteriosclerosis [4,12,17,18]. Even though 4-HNE is best known for its apoptotic and cytotoxic effects, it also has the potential to create DNA adducts, which in some cases can lead to mutations. 4-HNE, like other enals, forms exocyclic adducts after reacting with DNA nucleobases. The principal reaction

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Scheme 1. DNA damage induced by endogenously produced toxic aldehydes. Endogenous cellular processes such as lipid peroxidation, cell metabolism and glycation pathways generate aldehydic derivatives some of which exhibit high reactivity. The major DNA modifications caused by these electrophilic species are guanine adducts of malondialdehyde (MDA), exocyclic adducts with ␣,␤-unsaturated aldehydes and ethenobases. The ability of these reactive electrophiles to modify DNA bases, yielding promutagenic lesions, is considered to contribute to the mutagenic and pathogenic effects associated with the elevated levels of endogenously produced reactive aldehydes under stress conditions.

of enals with deoxyguanosine (dG) involves Michael addition of the N2 -amine to give N2 -(3-oxopropyl)-dG adducts, which yields the corresponding cyclic 1,N2 -dG products after cyclization of N1 with the aldehyde [12,13,19,20]. The 4-HNE exocyclic 1,N2 -dG adducts are summarized in Fig. 1A. These 4-HNE-DNA adducts have been used both as indicator of oxidative DNA damage but also as a biological marker for certain human diseases [20]. Studies have indicated that the lesions created from adducts of 4-HNE and similar aldehydes are found at frequency of 0.6–2000 per 109 guanines [19]. Not all of these adducts though are capable of forming interstrand DNA cross-links. Only the stereoisomer (6S, 8R, 11S)-HNE adduct possessing stereochemistry results in stable interstrand cross-linking formation [21]. Even though the 4-HNE interstrand cross-links can be potentially reversible [22], they have the ability to lead to mutation. The form adduct (6S, 8R, 11S)-HNE has been found to give 3.2% G → T transversions, 0.6% G → A transitions and 0.3% G → C transversions [19]. The assumption that 4-HNE is mutagenic in vivo has been confirmed by several findings. For example, several mutations created by the 4-HNE adducts have been reported in studies using liver specimens taken by patients with Wilson’s disease and hemochromatosis [19]. Furthermore, G → T transversion at codon 249 of p53 gene was found in lymphoblastic cells [12,23]. In COS-7 cells, 4-HNE led to base substitution (0.5–5% frequency) with the G → T to be the most common one [19,20]. Using a highly sensitive 32 P-postlabeling method in conjugation with high-performance liquid chromatography, the levels of 4-HNE-derived cyclic 1, N2 -propano-dG adducts were found approximately 37-fold increased (104 ± 22 nmol/mol guanine vs. 2.8 ± 1.8 nmol/mol guanine) in the liver DNA of rats after treatment with the carcinogen CCl4 , suggesting lipid peroxidation as a likely route of their formation [24]. Increased levels of 4-HNEderived DNA adducts were reported in human atherosclerotic lesions [25]. Lipid peroxidation related miscoding etheno-DNA adducts increased with time in chronically inflamed target organs in both humans and experimental animal models [26]. High content of DNA-etheno adducts has been associated with Krohn’s

disease, ulcerative colitis, chronic pancreatitis and inflammatory cancer-prone liver diseases [27,28]. Importantly, the presence of 4-HNE-DNA adducts is considered to be a potential cause of several neoplasias, including thyroid neoplasia and hepatocellular carcinoma [18,29,30]. The increased risk of thalassemia patients to develop hepatocellular carcinoma could be attributed to the accumulation of highly promutagenic 4-HNE-derived DNA lesions detected in these patients [31]. Finally, the role of 4-HNE-derived DNA lesions in the pathogenesis of degenerative diseases remains controversial [32,33]. 2.2. Acrolein Acrolein or propenal is an ␣,␤-unsaturated aldehyde that can originate from endogenous sources (carbohydrates consumption, LPO) or exogenous exposure to tobacco smoking and automobile exhaust [8,34]. Endogenous acrolein is produced by amino acids (methionine and threonine), polyamines, lipid peroxidation and also by the metabolism of cyclophosphamide, a drug administered for the treatment of cancer [34–36]. It is a highly reactive molecule that reacts with cysteine, lysine and histidine residues (especially strong bondage is created after lysine reaction) of proteins by blocking their sulfhydryl groups, thus leading to toxicity, cell proliferation transitions and blockage of intermediary metabolism [37–39]. Comparing to 4-HNE, acrolein is a minor byproduct of LPO that accounts for a small percentage of the acrolein found in the organism [34]. A lot of controversy exists about the actual production of acrolein from LPO and the relevant metabolic pathway involved. Most probably, acrolein originates from the oxidative degradation of linoleic or arachidonic acid from molecular oxygen [34]. Recent studies though support that acrolein is also produced from the ␻-3 polyunsaturated acids in the order of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA) and linoleic acid (LA), with DHA representing the main pathway of production and LA being the minor one [40]. The reaction includes two successive

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Fig. 1. Structures of DNA adducts induced by (A) 4-hydroxy-2-nonenal (4-HNE), (B) acrolein and (C) malondialdehyde.

␤-cleavages of the alkoxyl radicals that are produced at each step, leading to the formation of the aldehyde [34]. Acrolein’s main metabolism is via GSH conjugation in the liver and continues in the kidney, where the intermediate S-(3-oxopropyl)-N-acetylcysteine (OPMA) is produced. Further reduction of OPMA by aldo-keto reductase gives S-(3hydroxypropyl)-N-acetylcysteine (HPMA) and the oxidation of OPMA by an aldehyde dehydrogenase leads to the formation of S-carboxyethyl-N-acetylcysteine (CEMA) which is eventually excreted by the urine [34].

Acrolein reacts with DNA and creates adducts with dG generating 1, N2 -(-3oxopropyl)-deoxyguanosine by Michael addition [34,39,41]. The subsequent cyclization of the aldehyde and the N1 produces two regioisomeric adducts: ␣- and ␥-OH-PdG (Fig. 1B) [42]. While the ␥-OH-PdG appears to be the most frequent form found in vivo, it also has a higher ability to form DNA interstrand cross-links and also DNA–protein adducts. Such resulting DNA lesions are repairable by DNA polymerases’ complexes and thus have a lower mutagenic potential [34,42–44]. On the other side, even though the ␣-OH-PdG form is rare, it blocks the repli-

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cation of DNA and when the translation synthesis polymerase (TLS) manages to elongate through it, often leads to base substitution [35,43,45]. Acrolein-induced DNA adducts are preferentially induced at regions with high frequency of guanine nucleotides [43] and specifically in 5 -CpG-3 regions, something that can be explained by the methylation of the cytosine at site [43]. Common mutations caused by acrolein mainly lead to a G → C [34,35] and GC → TA transversions, and GC → AT transitions [35,43]. Acr-dG DNA adducts have been detected in animal and human tissues as common DNA lesions [46]. Studies have revealed a similarity between p53’s acrolein-induced DNA damage and gene mutations found in lung cancer specimens. This observation together with the capability of acrolein of blocking DNA repair mechanisms has classified this aldehyde as a major etiological agent for cigarette-smoke-related lung cancer. This assumption is in accordance with the elevated levels of acrolein-induced DNA damage found in smokers’ lung tissues [43]. In another study, exposure of liver epithelial cells to acrolein resulted in significant accumulation of the acrolein-2 -deoxyguanosine adduct in the nuclei and the formation of the same adduct was confirmed in an iron-induced carcinogenesis model in vivo [47]. Moreover, acrolein is also accused for the development of neurodegenerative diseases [48]. For example, in Alzheimer’s brain, acrolein was found to be elevated in hippocampus and temporal cortex, while a two-fold increase in levels of acrolein/guanosine adducts was isolated from the hippocampus of Alzheimeric mice as compared to age-matched control [45,49]. On the contrary, the levels of 4-HNE/guanosine adducts were not significantly altered in Alzheimeric mice compared to normal control subjects [50]. 2.3. Malondialdehyde (MDA) MDA is the predominant product of lipid peroxidation and is one of the most commonly used markers of oxidative stress. It is often found as a dimmer or trimmer due to its ability to act both as an electrophile and nucleophile [51], while at neutral pH exists as an enolate anion (a form characterized by low reactivity) [52,53]. Finally, MDA’s mutagenicity and carcinogenicity have been confirmed both in mammalian cells and in animals [54]. MDA is mainly produced when a polyunsaturated fatty acid with at least two methylene interrupted double bonds reacts with molecular oxygen, which leads to the production of peroxyl radicals [52,55]. The reduction of peroxyl radicals gives hydroperoxide through the cyclization of the internal peroxyl radical. When a second cyclization occurs, a bicyclic peroxide is produced, which after reaction with molecular oxygen produces an intermediate that subsequently gives MDA [55]. Although such pathway is considered to occur under conditions of stress, MDA can also derive from the same metabolic pathway that produces acrolein. More specifically, after tandem production of hydroperoxide and ␤-cleavages of the polyunsaturated fatty acid, the produced acrolein radical reacts with a hydroxyl radical leading to MDA formation [52]. In both cases, the produced MDA further diffuses to the entire cell and reacts with DNA and/or proteins (principally with their lysine residues) [56–58]. The mechanism for MDA’s metabolism in liver mitochondria is well defined: mitochondrial aldehyde dehydrogenase oxidizes MDA leading to the formation of malonate. The subsequent decarboxylation of malonate produces acetate and CO2 [59]. On the other site, the metabolism of malondialdehyde in the cytoplasm remains in part unclarified with MDA getting converted to methylglyoxal (MG) presumably by phosphoglucose isomerase [59,60]. Subsequently MG is enzymatically converted (by the enzymes glyoxalase I and II, and with GSH as a co-factor) to the neutral d-lactate [59,60]. MDA reacts with the N2 of the dG producing the aromatic molecule 1, N2 -deoxyguanosine pyrimidopurinone M1 dG (a fairly

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fluorescent molecule) (Fig. 1C), and with dA and dC leading to the formation of the non-cyclic oxopropenyl derivatives M1 dA and M1 dC [54,61]. While M1 dG possesses a close external ring configuration when it is opposite to a dT or on a single stranded DNA, the external ring opens through hydrolysis forming the noncyclic N2 -(3-oxo-1-propenyl)-2 -deoxyguanosine (N2 -OPdG) when it is opposite to a dC (Fig. 1C) [61–63]. Considering the percentage production the order of these adducts is: M1 dG > M1 dA > M1 dC, [54] with the M1 dG (detected in liver, pancreas, breast and leukocytes) [63] representing around 1–4 per 108 nucleotides in healthy individuals [64]. Interestingly, MDA-DNA adducts appear in much higher percentage at mitochondrial rather in nuclear DNA, possibly due to the absent of the nucleotide excision repair (NER) mechanism (the major mechanism responsible for the repair of the M1 dG) in mitochondrion [62]. Both forms of MDA-induced DNA adducts (with M1 dG to have a higher capability than OPdG) are able to induce mutations in mammalian cells: mainly G → A–T base pair substitutions as well as frame-shifts [61]. Finally, such MDA lesions are mainly bypassed by the members of Y-family of DNA polymerases hPol ␩ and Dpo4 (homologue of hPol ␬), which elongate DNA with low fidelity [61]. MDA has been associated with carcinogenesis and aging in humans [65–67]. For example, the MDA-dA and MDA-dG adducts have been found to be two–three fold increased in healthy tissue from breast cancer patients in comparison to specimens from healthy individuals [65,66]. Increased levels of M(1)dG adducts were observed in breast cancer patients and an obvious trend with increasing tumor grade and pathologic diameter was observed [68]. These results are consistent with the higher reported levels of MDAadducts in cancerous lung tissues compared to healthy lung tissues [69,70]. Moreover, percent formation of M1dG adducts is also used as a biomarker for the oxidative stress induced by exogenous stimuli and is connected with increased risk for cancer development [53]. Indeed, increased formation of M1dG has been observed in situations where oxidative stress was associated with bacterial infection, induction of inflammatory response and exposure to carcinogens in experimental animal models [71–73]. 2.4. Crotonaldehyde (Cro) Cro is produced through tobacco smoking, fuel consumption and lipid peroxidation [74,75]. During lipid peroxidation, Cro is produced mainly by the peroxidation of ␻-3 fatty acids [74,76]. Its ability to bind to GSH, with no subsequent metabolic initiation, leads to the accumulation of reduced GSH and induction of oxidative stress that could explain its apoptotic properties [76,77]. Cro reacts with DNA (by Michael addition and subsequent ring closure) to produce the stereoisomeric forms R-(6R, 8R) and S-(6S, 8S), ␣-CH3-␥-OH-1, N2 –propano-deoxyguanosine adducts (with the S configuration to be more favorable) (Fig. 2A) [74,78–82]. When the 1, N2 -dG adducts are located opposite of a dC or are located in double stranded DNA, they undertake an open ring conformation which leads to the formation of interstrand DNA cross-links [78,79,82,83]. In double stranded DNA, the cyclic and the ring-opened conformation occur in equilibrium [81]. Even though both R and S conformations are able to induce interchain cross-links, the R conformation can accomplish this more efficiently probably because it induces a lower disarrangement of the DNA conformation compared to the S stereoisomer [78,79,83]. Cro’s cross-linking with DNA has a very slow rate of formation, requiring weeks for the production of such DNA adducts [78]. Moreover, these adducts can further react with proteins and peptides and create DNA and protein cross-links [80]. Cro-DNA adducts have been found in human and rodents even after the exclusion of any Cro external sources [46,75,84]. In humans, Cro-DNA adducts have been detected at a ratio

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Fig. 2. Structures of DNA adducts induced by (A) crotonaldehyde (Cr), (B) 4-oxo-trans-2-nonenal (4-ONE) and (C) formaldehyde (FA).

of 0.01–2.11/106 of guanidine bases in liver, leukocytes and mammary gland [74], in placenta (26/108 nucleotides) [48] and leucocytes (6/108 nucleotides) [48]. Exposure to cigarette smoke has been reported to increase the levels of Cro-derived DNA adducts in human oral tissues [85]. The vectors pMY189 and PZ189 were used in human cells for the evaluation (by the supF gene) of the mutagenic potential of Cro and the common mutations reported were G → A and G → T transversions (with the S-stereoisomer to have a higher mutagenic potential than R), which are preferentially induced in 5 -AAGG-3 and 5 -CCTT-3 sequences [74,75,80,81]. Cro’s mutagenic and genotoxic properties have been studied in lymphoblastic human cells [75,79]. In addition, Cro is reported to induce mutations in Escherichia coli and Salmonella typhimurium, leading to chromosome aberrations (probably due to topoisomerase I, II and DNA synthesis inhibition) [82] and sister chromatide exchange in Namalva and CHO cells and inhibiting DNA replication in HeLa cells [86]. Moreover, Cro appears to have the capability of inducing atypical sperm formation in a dosedependent manner [86]. Concerning DNA replication, Cro-induced DNA lesions inhibit the bypass of DNA polymerase ␧, a process that is possibly accomplished by DNA polymerases ␫, ␬, ␨ with the protein Rev1 [75]. Cro’s ability to react with proteins (especially Lys residues) is associated with Alzheimer and other neurogenerative disorders [87]. Moreover, the development of airway neurogenic inflammations and chronic pulmonary disease has been attributed to Cro due to its ability to block the activity of detoxifying enzymes like aldehyde dehydrogenases [77]. 2.5. 4-Oxo-2-nonenal (4-ONE) 4-ONE is produced by the oxidation of ␻-3 and ␻-6 polyunsaturated acids (e.g. linoleic and arachidonic acid), which leads

to the formation of 13-hydroperoxides (13-HPODE) and eventually cis-unsaturated aldehyde 3(Z)-nonenal [88,89]. The latter gets dehydrated and through the intermediate 4-hydroperoxy-2(E)alkenal derivates 4-ONE [90–92]. This, in turn, is metabolized by the phase I pathway where it gets oxidized to 4-oxo-2-nonenoic acid (4-ONA) or reduced to 4-oxo-2-nonen-1-ol (4-ONO) [90,93]. Subsequently, both 4-ONE and 4-ONA/ONO are deactivated by GSH conjugation (through the contribution of GST) in phase II metabolism, in which the GSH conjugated intermediates result in mercapturic acid in the liver and kidney, which is further excreted through the urine [93]. 4-HNE is capable of interacting and creating covalent modifications with DNA and proteins mainly by Schiff base formation and Michael addition [94]. Moreover, it plays a significant role in cardiovascular disease and specifically atherosclerosis (where it has been reported to induce apoptosis in a dose-dependent manner in endothelial cells) [90], and chronic obstructive pulmonary disease [93]. Moreover, it has been characterized as genotoxic and cytotoxic and associated with many disease states including cancer (e.g. through triggering p53), neurodegenerative disorders, diabetes, post-ischemic reoxygenation injury, rheumatoid arthritis, and aging [91,93]. 4-ONE has the capability of cross-linking with proteins by reacting mainly with Cys, His and Lys residues [91,95–97]. Finally, it has an apoptotic effect on human cancer lines [98], possibly through the Fas/FasL apoptotic signaling pathway (p53-dependent) [95]. 4-Oxo-2-nonenal reacts with dG through a nucleophilic addition of N6 to the aldehyde’s C-1 and subsequent reaction of N1 and C-2 of the produced ketone [92]. This leads to the formation of a variety of etheno adducts, which are dehydrated to a sole heptanone etheno-dGuo adduct (Fig. 2B) [88,99]. Furthermore, 4-ONE interacts with dCyd, producing 7-(2-oxoheptyl)-etheno-dGuo adducts, which strongly blocks DNA replication and when by-passed by DNA

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polymerases, have a high miscoding potential with C → A and C → T substitutions to be the main mutations induced [100]. The reaction of dA with 4-ONE produces heptanone-etheno-2 -deoxyadenosine (H␧dA) (Fig. 2B) [99]. The formation of these adducts are produced at high rates when DNA is incubated with 4-ONE in vitro [88]. 4ONE was shown to induce the formation of substituted etheno-DNA adducts, H␧dC, H␧dA and H␧dG, both in cells and mouse models [101–103]. These adducts have been found to exist ubiquitous in various human tissues at median values of 10, 15 and 8.6 per 108 bases for H␧dC, H␧dA and H␧dG, respectively [99].

2.6. Formaldehyde (FA) FA is included in various environmental sources like, plywood, paper, cigarette smoke, cosmetics, paint, leather goods and even in various foods (e.g. fruits) [104,105]. It is also produced during the metabolism of various exogenous or endogenous substances (e.g. the metabolisms of serine, glycine, choline, histamine and l-methionine) [104,106]. The metabolism of FA is rather complicated: it is a substance for the alcohol dehydrogenase ADH1 (cytosolic), which reduces FA leading to the production of methanol [104]. Also, the mitochondrial aldehyde dehydrogenase ALDH2 and the cytoplasmic formaldehyde dehydrogenase ADH3 (GSH-dependent) oxidize formaldehyde producing formate [104]. FA has the ability to react with various biological targets and create DNA and protein adducts as well as DNA–protein crosslinks (DPCs) (the main DNA alteration induced by formaldehyde) [104–107]. In addition, FA has also been associated with chromosomal aberrations, micronuclei and sister chromatid exchanges [108–110]. Subsequently, it has a documented cytotoxic, genotoxic and carcinogenic action (mainly nasopharyngeal cancer and leukemias) and has also been linked with neurodegenerative diseases [104,105,108,110–113]. A wide variety of FA adducts with dA, dG and dC have been found mainly in vitro, probably due to the quick reaction of FA with GSH in cells [106]. Recent studies have shown the existence of N6 -HOCH2 -dAdo adducts and the dAdo-CH2 -dAdo cross-links, in animal tissues, after FA’s precursors administration in a dose-dependent manner [108]. The N6 -HOCH2 -dAdo adduct was also found in DNA samples of smokers, in significantly higher levels, compared with non-smokers [114]. On the other hand, DNA–protein cross-links are considered the main FA-induced DNA alterations [105,111]. FA is capable of creating such cross-links between Lys, His, Cys, Trp with the dG, dC and dA through an FA-derived methylene bridge or through a 1, N2 -fused triazino ring (mainly for the case of Lys-dG crosslink) (Fig. 2C) [105]. DPCs being preferentially created in cases of close DNA and protein interactions. For example, DNA-binding histones (high in Lys content) appear to form such cross-links when formaldehyde is present [105]. While DNA–protein crosslinks are considered unstable (due to the hydrolysis that often occurs spontaneously) when they remain in DNA, they can induce mutations, especially in proliferating cells [111]. DPCs have been detected in the nasal system of animals and in human lymphocytes exposed to FA [110]. Both endogenous and exogenous N2 -hydroxymethyl-dG adducts were detected in nasal DNA of rats exposed to various concentrations of FA with the exogenous FA-derived DNA adducts showing an exposure to FA-dependent increase [115]. FA’s mutagenicity has been studied in animals, where prolonged exposure to FA (through inhalation) led to increased tumorigenesis [116], while the carcinogenic effect was not evident when FA was administrated in water [109]. Finally, FA-induced DNA lesions are repaired by the homologous recombination pathway (HR) and the proteins REV1, REV3 and RAD18 [108].

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2.7. Methylglyoxal (MG) MG (Fig. 3A) is a byproduct of the ubiquitous pathway of glycolysis. It is either derived from the non-enzymatic fragmentation of triose phosphates (which include glyceraldehyde-3-phosphate and dihydroxyacetone phosphate) or it is produced enzymatically by reactions catalyzed by triosephosphate isomerase and methylglyoxal synthase [117]. Other sources of endogenous MG formation include (1) the metabolism of acetone or aminoacetone from lipolysis (catalyzed by semicarbazide-sensitive amine oxidase and acetol mono-oxygenase) and (2) the catabolism of the amino acids glycine and threonine. A slighter percentage of MG is also produced during degradation of DNA and lipid peroxidation [118–120,64]. MG is considered highly cytotoxic and because of such property there are several pathways that detoxify it within the cells. One of these pathways is the glyoxalase system. MG reacts with GSH (non-enzymatically) and produces a hemithioacetal, that subsequently leads to the formation of S-d-lactoyl-glutathione (by the action of the enzyme glyoxalase I) which is then further hydrolyzed to GSH and lactic acid (by the action of glyoxalase II) [121,60]. Moreover, MG has been associated with uremic and diabetic complications, like nephropathy, retinopathy and atherosclerosis [118,121–124,64,125–128]. More specifically, MG was found at higher rates in the blood of diabetes patients, in the kidney of patients with diabetic nephropathy and in the aorta of uremic atherosclerosis patients [129,130]. Furthermore, MG is considered a cause of retinal pericyte damage and subsequent blindness [130]. MG reacts with the nucleophilic moieties of DNA, lipids and proteins (mainly through arginine, lysine and cysteine residues) producing advanced glycation end products (AGEs) that have been linked with damaging of the immune system (through IgG interactions) and cataract development [120–123,127,131]. Through its ability to form protein adducts, MG has also been associated with Alzheimer disease and aging [119,132]. MG was shown to induce apoptosis through the induction of oxidative stress and ROS formation [129] in human podocytes, bovine retinal pericytes and human vascular endothelial cells [122]. The most important MG-induced DNA adducts are the R- and S-N2 -(1-carboxy ethyl)2 -deoxyguanosine CEdG, from the addition of MG to the N1 and N2 of dG (Fig. 3A) [119,125,127,130]. CEdG adducts are considered an important risk factor for the development of cancer and have been detected in WM-266-4 human melanoma cells (one lesion per 107 bases) [130]. Only recently, have the CEdG adducts been studied for their ability to induce mutations in vitro. In such studies, DNA polymerases Taq and Klenow preferentially incorporate purines opposite to CEdG adducts, something that is further enforced by the elevated G transversions occurred after exposure to increased glucose levels [119]. Upon interaction of methylglyoxal with DNA, more adducts are formed such as the bis-adduct N2 , 7-bis(1hydroxy-2-oxopropenyl)-dGuo and the diastereomeric mixtures of imidazopurinone [3-(2 -deoxyribosyl)-6,7-dihydro-6,7dihydroxy-6/7-methylimidazo-(2,3-b)purine-9(8)one (MGdG)] (Fig. 3A) [64,124,131]. The latter, was associated with apoptotic onset and induction of DNA strand breaks and high levels were reported in tumor cell lines (in vitro) and in mononuclear leukocytes (in vivo) [124]. Recently, another adduct has been reported, which is produced by the MG, malondialdehyde and dA reaction leading to the formation of 8-(diformylmethyl)-7-methyl-3-(␤-dribofuranosyl)imidazo[2,1-i]purine (M1 MGx-A), an adduct found in vitro, after the incubation of the above aldehydes with DNA from calf thymus (Fig. 3A). 2.8. Glyoxal (Gx) Gx is produced during the spontaneous reaction of amino groups in proteins with (1) reducing sugars (Maillard reaction),

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Fig. 3. Structures of DNA adducts induced by (A) methylglyoxal (MG), (B) glyoxal (Gx) and (C) acetaldehyde (AA).

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(2) sugar auto-oxidation, (3) polysaturated fatty acid peroxidation and (4) microsomal oxidation of glycolaldehyde and ␤-hydroxysubstituted N-nitrosamines [133,117]. Although glyoxal can form adducts with 2 -deoxyadenosine, 2 -deoxycytidine, and cytidine, it shows a preference for interacting with the guanine moiety to form diastereoisomers of 3-(2 -deoxy-␤-d-erythro-pentafuranosyl)5,6,7-trihydro-6,7-dihydroxyimidazo[1,2-a]purin-9-one; (Gx-dG); Fig. 3B) [134,135]. Structures of coupling products of nucleosides with Gx-dG were recently elucidated [136], and new, stable glyoxal-2 -deoxyguanosine adducts were characterized [137]. A new malonaldehyde–glyoxal adduct was recently identified as 8-(diformylmethyl)-3-(␤-d-ribofuranosyl) imidazo[2,1-i] purine (M1Gx-A; Fig. 3B) [64]. The formation of this adduct has been observed in calf thymus DNA after incubation with the respective aldehydes at physiologic pH and temperature [64]. Given the concurrent presence of glyoxal and methylglyoxal in the tissues, the formation of M1Gx-A conjugate adduct, in biological systems, could not be ruled out. However, the contribution of the M1Gx-A adduct in the formation of DNA lesions and its physiological significance remains to be elucidated. 2.9. Acetaldehyde (AA) AA (Fig. 3C) is mainly produced by the metabolism of alcohol, cigarette smoking, diesel or automobile exhaust and as an intermediate in sugar’s metabolism. It is considered to be responsible for the pathological complications of alcohol consumption [138–141]. During ethanol metabolism, (mainly occurring in liver) alcohol dehydrogenase-ADH (ADH1B, ADH1C), CYP2E1 and catalase oxidize ethanol to acetaldehyde, which is further oxidized by aldehyde dehydrogenase (ALDH2) or cytochrome P450 2E1 to acetate [142–144]. Some of the alcohol drinking complications including cancer (of oral cavity, larynx, oesophagus, pharynx, liver, breast and colorectal) have been associated with increases in AA formation due to ethanol consumption or inadequate enzymatic capacity towards AA detoxification (e.g. ALDH2 polymorphisms) [138,142,145,146]. For example, the risk of oesophageal cancer formation (especially squamous cell carcinoma) is considerably increased by alcohol consumption and cigarette smoking, especially in ALDH2deficient individuals which represent 8% of population [147,148]. Administration of AA by inhalation resulted in nasal and larynx cancer formation in rats and hamsters [149]. In another study, chronic exposure to acetaldehyde, via inhalation, caused increased levels of nasal and laryngeal tumors in rats and hamsters [150]. AA is considered teratogenic, genotoxic and mutagenic, due to its ability to react with DNA (with dA, dC, but mainly dG) producing as main adduct the: N2 -ethylidenedeoxyguanosine (N2 ethylidene-dG) and its reduced form N2 -ethyldeoxyguanosine (N2 -ethyl-dG) (Fig. 3C) [138,143,151,152]. The latter has been detected at elevated levels in animal models of alcohol exposure and in white blood cells of human alcoholics [153,154]. Furthermore, higher rates of N2 -ethylidene-dG adducts were measured in Aldh2−/− , in comparison with Aldh2+/+ mice after treatment with ethanol or AA [142,155,156]. Studies have shown that several additional adducts can be formed from AA and DNA. Amongst them are the ␣-S/␣-R-methyl-␥-hydroxyl1, N2 -propano-2 -deoxyguanosine (␣-S/␣-R-Me-␥-OH-PdG) and the N2 -(2,6-Dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N2 -DiodG) (Fig. 3C) [157]. Recent data have shown that the levels of the three acetaldehyde-derived DNA adducts, N2 -Et-dG, ␣-S-Me␥-OH-PdG, and ␣-R-Me-␥-OH-PdG, were significantly higher in alcoholics with the ALDH2*1/2*2 genotype compared to those with the ALDH2*1/2*1 genotype [145]. In the presence of basic molecules and histones, AA reacts with deoxyguanosine in DNA to form the 1,N2 -propano-2 -deoxyguanosine (PdG) adduct [158,159]. The

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latter has been shown to be a mutagenic DNA lesion in mammalian cells in vivo at the range of AA concentrations from 40 to 1000 ␮M [157]. Through the process of adducts formation AA induces the production of inter-strand DNA cross-links (by the reaction of two aldehyde molecules), which block DNA recombination and replication [143], base substitutions (G → A and A → T), splice mutations and frame-shifts [160]. Responsible for the repair of AA-induced DNA cross-links are the homologous recombination repair (HRR) and the nucleotide excision repair (NER) pathways [140]. Finally, AA also reacts with RNA, proteins and phospholipids and is capable of inducing DNA–protein adducts formation (not as radically as FA) and causes sister chromatin exchange, aneuploidy and micronuclei both in mammalian and bacterial cells [139,140,144,145,150]. 2.10. Glyceraldehyde (GA) GA is produced during glycolysis and through fructose metabolism [161]. In the latter, fructose produces fructose1–phosphate (F-1-P) through phosphorylation, and F-1-P in the liver, further leading to the formation of dihydroxyacetone phosphate and GA by the enzyme aldolase B [161]. Although GA’s interaction with DNA has been mainly studied in vitro [162–165], it is believed that GA reacts with 2 -deoxyguanosine and produces DNA-bound advanced glycation products (DNA-AGEs) like N2 -(1-carboxy ethyl)-2-deoxyguanosine (CEdG) [162,166]. Evidences of increased formation of this DNA adduct were found in kidney and aorta samples from diabetic nephropathy and diabetic patients [166]. GA also attacks proteins, through interactions between the amino group of the residues and the carbonyl group of GA [163]. By this interaction a Schiff base is produced, which subsequently rearranges to a ketoamine [161,163]. When glyceraldehyde interacts with lysine it has the potential to induce DNA–protein cross-links, for example N6 -[2(N2 -Deoxyguanosyl)-propionyl]-lysine [166]. Ketoamines are the offset of several glycation end-products, which are considered to have a key role in Alzheimer disease and diabetes’s complications [161,163]. 2.11. Detection of aldehydes-induced DNA adducts During the last years sensitive and specific methods have been developed to facilitate the detection and quantitation of aldehyde-derived DNA adducts in human tissues and clinical samples, where they can be detected as modified bases and nucleosides. Besides their contribution in studying and characterizing the aldehydes-derived DNA adducts, these methods have facilitated their detection in vivo and have greatly enhanced our knowledge of their role in disease pathogenesis. Immunohistochemical detection, immunoaffinity-32 Ppostlabeling, high-performance liquid chromatography with electrochemical detection, gas chromatography–mass spectrometry, and liquid chromatography–tandem mass spectrometry are the main methods that are currently used for the detection of aldehyde-DNA adducts. The analytical methods used in DNA adduct analysis have been recently reviewed [20,167]. The accuracy of the above methods has been questioned and detection of artefactual formation or loss of DNA adducts during isolation and analysis can affect the estimation resulting in imprecise measurement of DNA damage [10,168–170]. Nevertheless, the techniques are constantly under development for their improvement in matter of efficiency and specificity and are generally considered valuable and reliable tools. Validation of some of these methods in humans has resulted in useful biomarkers for disease risk assessment and biomonitoring [20].

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Table 1 Evidence of aldehyde-derived DNA adduct accumulation in animal and human tissues and relation to pathophysiology. Aldehyde

Source

Major aldehyde-derived adducts

Related pathophysiology and major findings

4-HNE

Lipid peroxidation

N2 -(3-oxopropyl)-dG

Inflammation: High content of DNA etheno-adducts in affected tissues of patients suffering from Krohn’s disease, ulcerative colitis and chronic pancreatitis [27]; Etheno-DNA adducts increased in organ, blood or urine of patients with cancer-prone diseases related to persistent inflammatory processes, e.g. Wilson’s disease, cirrhosis and hepatocellular carcinoma [26]; Subjects with inflammatory cancer-prone liver diseases caused by viral infection or alcohol abuse excreted in the urine massively increased ␧dA levels [28].

1, N2 -dG 1,N6 -ethenodeoxyadenine (␧dA)

Thalassemia: ␧dA and ␧dC lesions were found higher (9-fold and 13-fold, respectively) in ␤-Thal/Hb E patients compared to asymptomatic controls, suggesting that these highly promutagenic lesions may contribute to the increased risk of thalassemia patients to develop hepatocellular carcinoma [31].

3,N4 -ethenodeoxycytosine (␧dC)

Acrolein

MDA

Lipid peroxidation

␣-OH-PdG

Metabolic reactions Environmental sources

␥-OH-PdG

Lipid peroxidation

M1dG

M1dA M1dC

Arteriosclerosis: High levels of DNA etheno-adducts were detected in human atherosclerotic lesions [25]. Degenerative diseases: Higher levels of ␧dA were detected in old OXYS rats compared to age-matched Wistar rats correlating with the known shorter life-span and elevated frequency of chronic degenerative disease of OXYS rats [32]; Although 1,N2- propanodeoxyguanosine adducts of 4-HNE are distinctively present in the human brain, the levels of HNE-dGp adducts remained unaltered in Alzheimer’s disease (AD) leading to the assumption that HNE-dGp adducts appear not to be a useful biomarker for AD [33]. Carcinogenesis, neoplasias: An approximately37-fold increase was observed in N2 -dG-propano-DNA adducts in the liver DNA of rats after treatment with the carcinogen CCl4 [24]; 4-HNE preferentially forms DNA adducts at codon 249 of human p53 gene suggesting that 4-HNE-induced DNA lesions may be an important etiological factor for human cancers that have a mutation at the specific locus, such as hepatocellular carcinoma [30]; Cytoplasmic 8-oxo-dG and 4-HNE expression were significantly higher in human thyroid adenomas and carcinomas compared to matched normal tissue [29]. Carcinogenesis: Exposure of rat liver epithelial cells (RL34) to acrolein resulted in significant accumulation of the acrolein-2 -deoxyguanosine adduct in the nuclei. The formation of the above DNA adduct in vivo was further confirmed in the nuclei of the proximal tubular cells of rats exposed to the carcinogenic iron chelate nitrilo triacetate [47]. Neurodegenerative diseases: Elevated levels of acrolein were detected in hippocampus and temporal cortex in AD brains whereas in late onset of the disease a two-fold increase in levels of acrolein/guanosine adducts in nDNA were isolated in the hippocampus of AD as compared to age-matched control suggesting that acrolein may play a role in the pathophysiology of AD [45,49]. Exposure to tobacco: Oral tissues of cigarette smokers have significantly higher Acr-dG DNA adducts levels compared to non-smokers [85] Neoplasias: Using 32 P-DNA post labeling techniques, the formation of MDA-DNA adducts was found increased in larynx cancer patients compared to control. Smoking and alcohol were found to further influence the production of these endogenous adducts in larynx tissues [69,70]; Using the same methods, MDA-DNA adducts were quantified in specimens of normal breast tissues of cancer patients and healthy subjects. Normal breast tissues of cancer patients contained approximately three-fold higher levels of lipid peroxidation-related DNA adducts compared to non-cancer controls [65]; Increased levels of M(1)dG adducts were observed in women with breast cancer with a present trend with increasing tumor grade and pathological diameter [68]. Carcinogenesis: Using an experimental model of mouse liver carcinogenesis, the increased formation of M1dG observed as a result of oxidative stress associated with Helicobacter hepaticus infection of mice was hypothesized to contribute to liver carcinogenesis in this model [71].

N2 -OPdG

Cro

Lipid peroxidation

R-/S-␣-CH3-␥-HOPdG

Inflammation: In studying the transcriptional responses of the lung in acute inflammatory response, a significant correlation was observed between the differentially expressed gene list and the promutagenic DNA lesion M1dG in mouse lung tissue exposed to LPS [72]. Aging: Indigenous DNA adducts (I-compounds) are biomarkers of aging tissue and have been reported to increase with aging. In an effort to characterize these I-compounds, five dGMP-DNA adducts were identified in rat brains that increased three,five-fold from 6 to 24 months of age [67]. Exposure to toxicants: Accumulation of M1dG DNA adducts was evidenced after chronic exposure of mice to the carcinogen polychlorinated biphenyl(PCB) supporting the hypothesis that DNA damage plays a key role in the PCB-induced toxicity and carcinogenicity [73]. Normal tissue: Using a 32 P-postlabeling method combined with HPLC the presence of Cro-derived exocyclic adducts (1,N2 -propano-2 -deoxyguanosine adducts) was detected in common lesions in the liver DNA of rodents and humans suggesting that lipid peroxidation is an endogenous process for their formation [46,84]; Cro-derived DNA adducts were detected in detected at a ratio of 0.01–2.11/106 of guanidine bases in liver, leukocytes and mammary gland [74]; Using isotope dilution nanoflow LC nanospray ionization tandem mass Cro-derived DNA adducts were detected in human placenta (26 per 108 nucleotides) and leukocytes (6.2 per 108 nucleotides) [48].

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Table 1 (Continued) Aldehyde

Source

Major aldehyde-derived adducts

Related pathophysiology and major findings

Environmental sources

4-ONE

FA

Lipid peroxidation

H␧dG

Environmental sources

H␧dC H␧dA Cys-CH2 -dG

Metabolic reactions

MG

Gx

Glycolysis

Lys-CH2 -dG CEdG

Metabolic reaction Lipid peroxidation

dGuo MGdG

Lipid peroxidation

M1 MGx-A Gx-dG

Glycolysis

AA

Alcohol metabolism

Environmental sources Metabolic reactions GA

His-CH2 -dA Trp-CH2 -dG

Glycolysis

dA-gx-dG dC-gx-dG dG-gx-dG M1 Gx-A N2 -ethylidene-dG

N2 -ethyl-dG A-S/␣-R-Me-␥OH-PdG N2 -Dio-dG CEdG

Exposure to tobacco: Using a 32 P-postlabeling method combined with HPLC, Cro-derived DNA adducts were detected in oral tissue DNA at much higher levels in smokers compared to non-smokers [85]. Elevated levels of 4-ONE have been associated with various disease states including cardiovascular diseases, chronic obstructive pulmonary diseases, post-ischemic reoxygenation injury, rheumatoid arthritis, neurodegenerating diseases, diabetes, neoplasias and aging [88,91–94]. Only recently has the detection of 4-ONE-derived DNA adducts been reported in human tissues. By using liquid chromatography–tandem mass spectrometry, adductome analysis revealed that adducts H␧dC, H␧dA and H␧dG exist ubiquitously in various human tissues at median values of 10, 15 and 8.6 per 108 bases, respectively. Importantly, extremely high levels (more than 100 per 108 bases) of these adducts were detected in different human autopsy samples from different individuals [99].

Carcinogenesis: In a FA-induced rat carcinogenesis model, high levels of N2 -hydroxymethyl-dG monoadducts and dG–dG cross-links in DNA were detected in rat respiratory nasal mucosa using liquid chromatography–tandem mass spectrometry [113]; Using liquid chromatography-electrospray ionization–tandem mass spectrometry the FA-derived DNA adduct N6 -OHMe-dAdo was found at much higher levels in leukocyte DNA samples of smokers compared to non-smokers suggesting an important role of FA as a cause of tobacco-induced cancer [114]. Exposure to FA: Using a highly sensitive nano-UPLC-MS/MS method, both endogenous and exogenous N2 -hydroxymethyl-dG adducts were detected in nasal DNA of rats exposed to different concentrations of FA. While both the endogenous and exogenous FA-derived DNA adducts were detectable, exogenous DNA adducts demonstrated an exposure to FA-dependent increase [115]. Cancer: N2 -CEdG was detected in WM-266-4 human melanoma cells at a frequency of one lesion per 107 nucleosides. Treatment of cells with MG or glucose led to a dose-responsive increase in N2 -CEdG formation [130]; Advanced glycation end products of DNA (CEdG) were detected in human breast tumor at levels 3–12 adducts/107 dG [131]. Exposure to MG: Exposure of human leukocytes and tumor cells to MG resulted in accumulation of the MG-derived imidazopurinone MGdG suggesting that imidazopurinones are a major type of endogenous DNA damage [124] Implicated in aging, age-related diseases, diabetes and atherosclerosis but no direct studies yet performed [171,172].

Alcohol-related disease: AA-DNA adducts (N2 -ethyl-dG) were detected with 32 P-postlabeling in liver DNA from mice treated with ethanol at an average concentration 1.5 ±0.8 adducts/108 nucleotides by reverse-phase HPLC [153]; Using the same methodology higher levels (7–13-fold) of AA-DNA adducts were detected in peripheral white blood cells of alcoholic abusers compared to control subjects [154]; The levels of the three acetaldehyde-derived DNA adducts, N2 -Et-dG, ␣-S-Me-␥-OH-PdG, and ␣-R-Me-␥-OH-PdG, were significantly higher in alcoholics with the ALDH2*1/2*2 genotype compared to those with the ALDH2*1/2*1 genotype [145]; Higher rates of hepatic and gastric N2 -ethylidene-dG adducts were measured in Aldh2−/− mice compared to Aldh2+/+ mice [142,156].

Implicated in Alzheimer disease and diabetes but not direct studies yet performed [162,163,166]

Metabolism

3. Conclusions Evidence has been accumulated that aldheyde-induced DNA adducts play a major role in several human diseases (Table 1). Since they act as promutagenic DNA adducts they could be useful biomarkers for investigating the role of lipid peroxidation and oxidative stress in human disease correlating lifestyle and disease state. Furthermore, aldehyde-induced DNA adducts could be used as diagnostic markers for disease progression and disease risk assessment. Future studies need to elucidate the mechanistic aspects of the involved cell repair mechanisms and investigate potential pre-

ventive strategies that could alleviate related disease by lowering levels of aldehyde-derived DNA adducts. Conflict of interest None.

Acknowledgments This work was supported, in part, by the National Institutes of Health (Grant P20RR17675), Centers of Biomedical Research Excellence (COBRE) and Layman Award from the University of

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G.-P. Voulgaridou et al. / Mutation Research 711 (2011) 13–27

Nebraska-Lincoln (Dr. Franco), a Marie Curie International Reintegration Grant within the 6th European Community Framework Program (MIRG-CT-2006-036585) (Dr. Pappa), and the School of Community Health Sciences and a Junior Faculty Research Award from the University of Nevada-Reno (Dr. Panayiotidis).

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