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CIGARETTE SMOKE AND OXIDATIVE STRESS

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149

CIGARETTE SMOKE AND OXIDATIVE STRESS

Chemical and physical hazards and lifestyle factors (e.g., smoking, alcohol consumption, and diet) contribute to many

of the chronic diseases including cancer. Endogenous exposures from products of metabolism and pathophysiologic inflamma- tion are also contributory factors.

1∼3)

Oxidative stress refers to the imbalance between generation of reactive oxygen species and the activity of the antioxidant defences and the mecha-

Oxidative Damage and Chronic Inflammation Induced by Smoking: Potential Antioxidant and Peripheral

Biomarker Considerations

Okezie I Aruoma1, Kyung-Sun Kang2, Theeshan Bahorun3, Mi-Kyung Sung4, Irfan Rahman5

1Faculty of Health and Social Care, London South Bank University, London SE1 0AA, United Kingdom, 2Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea, 3Department

of Biosciences, Faculty of Science, University of Mauritius, Réduit, Republic of Mauritius, 4Department of Food and Nutrition, Sookmyung Women's University, Seoul 140-742, Korea, 5Department of Environmental Medicine,

University of Rochester Medical Center, Rochester NY14642, USA

Several studies indicate that oxidative stress and inflammation are features of smoking related disorders.

Active smoking can cause respiratory disorders culminating in chronic obstructive pulmonary disease (COPD), cardiovascular hazards, and cancer. Lung cancer results from man-made and natural environ- mental exposures acting in concert with both genetic and acquired characteristics. Genetic polymorphisms that affect xenobiotic metabolism or cellular response to DNA damage can modulate individual sensitivity to genotoxins. Endogenous antioxidant defences are often inadequate to scavenge free radicals (contained in cigarette smoke), reactive oxygen (ROS) and reactive nitrogen species (RNS) completely and ongoing oxidative damage to DNA, lipids, proteins, and other biomolecules is suggested to contribute to the pa- thology of many human degenerative diseases. The phenolic compounds in plant extracts are mostly deri- vatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids.

These are accessible to consumers through diet, their multifunctional nature (in particular flavonoids) makes them ideal candidates as prophylactic agents. There is a need to define if the presence of oxidative stress induced by smoking could be attenuated by the administration of antioxidant compounds and if this relationship could be linked to the presence of a particular genetic polymorphism and modulation of the complex cell signalling cascades involving gene transcription. (Cancer Prevention Res 10, 149- 158, 2005)

ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Key Words: Cigarette smoke, DNA damage, Cancer, Inflammation, Oxidative stress, Dietary antioxidants,

Oligonol, Cancer chemoprevention

Correspondence to:Okezie I Aruoma

Faculty of Health and Social Care, London South Bank University, 103 Borough Road, London SE1 0AA, UK

*OIA is Adjunct Research Professor, Faculty of Science, University of Mauritius, Reduit, Mauritius and Visiting Professor at the College of Veterinary Medicine, Seoul National University, Seoul, Korea

Tel: +44-20-7518-7927 E-mail: aruomaoi@lsbu.ac.uk 책임저자:Okezie I Aruoma

Faculty of Health and Social Care, London South Bank University, 103 Borough Road, London SE1 0AA, UK Tel: +44-20-7518-7907

E-mail: aruomaoi@lsbu.ac.uk

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nisms of the biological interactions are implicated in a variety of diseases (Fig. 1).

4∼6)

The importance of oxidative stress injury is dependent on the molecular target, the severity of the stress and the mechanism by which the oxidative stress is imposed i.e. drug induced, Fenton chemistry, trauma, enzyme activation (e.g. nitric oxide synthase activity) and the cellular transduction mechanisms, which may affect the expression of certain proteins including the DNA repair enzymes.

4∼7)

Smokers and patients with COPD

8,9)

have increased oxidative stress impetus. This is not surprising for indeed, cigarette smoke is a complex mixture of over 4,700 chemical compounds, in- cluding high concentrations of oxidants, free radicals and various reactive constituents, such as acrolein, acetaldehyde and benzo(a)pyrene.

2,10)

The superoxide anion (O

2•-

) and nitric

oxide (NO) predominantly found in the gas-phase react rapidly to form the highly reactive peroxynitrite (ONOO

-

) molecule.

The radicals in the tar phase of cigarette smoke are long-lived, such as semiquinone radicals. They can also react with O

2•-

to form hydroxyl radical (

OH) and H

2

O

2

.

10)

The aqueous phase of the cigarette smoke may undergo redox recycling for a considerable period of time in epithelial lining fluid (ELF) of smokers.

2,10)

The tar phase is also an effective metal chelator and can bind iron to produce tar-semiquinone + tar-Fe

2+

, which can generate H

2

O

2

continuously. Sidestream cigarette smoke contains more than 10

17

reactive organic compounds per puff, such as carbon monoxide, nicotine, ammonia, formaldehyde, acetaldehyde, crotonaldehyde, acrolein, N-nitrosamines, benzo (a)pyrene, benzene, isoprene, ethane, pentane and other geno- toxic and carcinogenic organic compounds.

1,2,10)

Although oxidant burden in the lungs is enhanced in smokers by the release of ROS from macrophages and neutrophils, lung cancer results from man-made and natural environmental exposures acting in concert with both genetic and acquired characteristics.

Other factors, such as air pollutants, infections, and occupational dusts that may exacerbate COPD, also have the potential to produce oxidative stress.

Most tobacco carcinogens require phase I and phase II enzymes for their activation and detoxification. Therefore, genetic polymorphisms in genes involved in carcinogen meta- bolism may regulate lung cancer susceptibility.

11)

However, no definitive association between. polymorphisms of major tobacco related carcinogen activating enzymes including CYP1A1,

Fig. 2. Oxidative stress-mediated lung injury and inflammation lead- ing to lung cancer.

Fig. 1. Consequences of reactive oxygen species in lung cancer.

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CYP2E1 or CYP2D6 and lung cancer risk.

12)

Also, The role of detoxification enzymes such as GSTM, GSTT1 and GSTP1 in modifying lung cancer risk remains controversial.

13)

A recent meta- analysis review indicated that genetic polymorphisms in myeloperoxidase gene and epoxide hydrolase are significantly associated with lung cancer risk.

12)

OXIDATIVE STRESS AND PRODUCTS OF DNA AND LIPID DAMAGE

In living cells, there is a steady formation of DNA lesions.

Free radical attack upon DNA generates a series of modified purine and pyrimidine base products. The DNA adduct 8-oxo- 7,8-dihydroguanine (8-oxoGua) results from the attack of

OH On guanine. The hydroxyl radical first reacts with guanine to form a C8-OH adduct radical. The loss of an electron (e

-

) and proton (H

+

) generates 8-oxoG. The C8-OH adduct radical may also be reduced by uptake of an electron and a proton forming 7-hydro-8-hydroxyguanine which is subsequently converted to 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FaPy). The formation of 8-oxoGua residues in DNA leads to GC:TA transversions unless repaired prior to DNA replication and this may lead to point mutations.

7,14,15)

The most common damage to pyrimidines is the formation of thymine glycol (Tg) which results from radical attack by hydroxyl radical to yields 5-hydroxy-6-peroxyl-radical. In the absence of oxygen, loss of an electron followed by uptake of water and loss of a proton generates thymine glycol. In the presence of oxygen, attack at position 6 first yields a 5-

hydroxy-6peroxyl radical, which is converted to thymine glycol through loss of a proton and superoxide anion and reaction with water. Indeed 5-methylcytosine (5-meC) can also be converted to thymine glycol by ionising radiation under aerobic conditions or H

2

O

2

and may thus be an additional source of mutations in organisms that utilise 5-meC to regulate gene expression. The level of the modified bases in vivo can depend on oxidative DNA insult and can be reflective of an involvement of different repair mechanism(s).

7,14,15)

Increased levels of modified DNA bases may contribute to the genetic instability and metastatic potential of tumour cells in fully developed cancer. A direct correlation between 8-oxoGua formation and carcinogenesis in vivo as well as the induction of mutagenesis in hotspot codons of the human p53 and Ha-ras genes are widely suggested. Indeed cancer patients are known to show signs of extensive granulocyte activation with a release of ROS and increases in the levels of 8-isoprostane, one of the biomarkers of oxidative stress. Our research data also shows that exposure of cells to cigarette smoke and to oxidants can lead to oxidative damage to DNA bases (Figs. 3, 4).

16,17)

Given that dietary components in plants (illustrated in Fig. 5 by hydroxytyrosol from olive oil) are able to modulate oxidative DNA damage,

18)

the ability of antioxidant supplements in modulating oxidative DNA damage due to cigarette smoke and hence facilitate the disease management, can be similarly assessed. However caution needs to be exercised when extra- polating the studies to smokers. This is heavily illustrated with the debate on β-carotene which has been shown to be protective in non-smokers but can cause cancer in smokers.

19∼22)

Fig. 3. Exposure of cells to cigarette produce significant changes in DNA base products. Spencer, Jenner Chimel, Aruoma, Cross, Wu and Halliwell, FEBS Lett 375, 179-182, 1995.

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Cigarette smoke via its oxidative components interact with membrane phospholipids, induces formation of the specific membrane lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) which is known to activate cell signaling pathways.

Smokers have elevated levels of F

2

isoprostanes compared with control non smokers.

23)

This may be linked to the increased activation of phospholipase A

2

activity leading to increased oxidation of arachidonic acid in vivo. F

2

-isoprostanes are a family of eicosanoids produced by non-enzymatic free radical

oxidation of arachidonic acid esterified to phospholipids.

F

2

-isoprostanes are produced in the esterified form in tissues and rapidly hydrolyzed to the free acid form, which later enters the circulatory system. F

2

-isoprostanes are quickly removed from the circulation.

24)

Measurement of F

2

-isoprostanes and their metabolites is considered to be a reliable marker for assaying lipid peroxidation in vivo and is widely recommended for studies of lipid peroxidation in human diseases and for assess- ment of the in vivo effects of antioxidants

Fig. 4. Effect of hydrogen peroxide on DNA in human respiratory tract epithelial cells. Spencer. Jenner Chimel, Aruoma, Cross, Wu, and Halliwell, FEBS Lett 375, 233-236, 1995.

Fig. 5. (A) Effect of increasing concentrations of hydroxytyrosol on the yield of oxidized DNA base products following the treatment of neuronal cells [The neuronal hybridoma cell line N-18-RE-105 (primary rat embryonic retinal cell × mouse neuroblastoma cell)]

with peroxynitrite (1 mM). (B) Shows the levels of hypoxanthine and xanthine, the deamination products of adenine and guanine respectively.

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CELL PROLIFERATION, DNA INTEGRITY AND CIGARETTE SMOKE

Homeostasis of cell proliferation and cell death plays an essential role in the maintenance of the function of organs and organisms.

25,26)

Interestingly, this is thought to be characteris- tically unbalanced without adverse consequences during embr- yonic development, establishment of immunologic tolerance, and during regeneration.

27,28)

However, imbalance can also lead to adverse consequences such as the clonal expansion of malignancy when cells become resistant to apoptosis or proliferate excessively. Conversely, excessive cell death and/or diminished proliferation may be deleterious. Such imbalance occurs in degenerative diseases like AIDS, ischemia, toxin- mediated or autoimmune diseases, and in some types of cancer.

27,29)

It has been argued that the relative rates of cell death and cell proliferation may vary as malignancy pro- gresses.

27,30)

During physiological apoptosis, most of the cell death pro- ducts are effectively removed by macrophages and neighbouring cells and can be found in the circulation only in small amounts.

26)

Similarly, during apoptosis, chromatin is characteristically cleaved into mono- and oligonucleosomal fragments that are released into the circulation after disintegration of the cellular mem- brane.

26)

Given that the amount of circulating DNA may have prognostic significance in various cancers, the extent of these early changes of circulating DNA fragments predict the res- ponses to therapy.

Cigarette smoke-derived free radicals/oxidants have been shown to damage DNA, e.g. incubation of bacteriophage DNA with buffered aqueous extracts of cigarette tar results in a dose-dependent production of single-strand breaks in DNA.

Cigarette smoke condensate-mediated DNA strand break is protected by

OH radical scavengers suggesting that the

OH is responsible for DNA nicks caused by cigarette smoke condensate.

31)

Quinones in cigarette smoke condensates (CSC) can form complexes with or becomes bonded to DNA suggest- ing that CSC acts as a site- or base-sequence-specific DNA cleavage agent. Bermudez et al have shown that tar component in sidestream cigarette smoke produces DNA nicks which was prevented by glutathione in rat alveolar macrophages.

32)

Similarly Izzotti et al

33)

have shown that N- acetylcysteine inhibited the carcinogen-DNA adducts in the tracheal

epithelium of rats exposed to cigarette smoke.

Chronic cigarette smoking increases the number of neutro- phils in lung fluid and organic compounds such as catechol and hydroquinone which may activate these cells to produce in- creased amount of ROS. Leanderson and Tagesson

34)

have reported that neutrophils can cause oxidative DNA damage (formation of 7-hydro-8-oxo-2’deoxyguanosine (8-oxodG) in alveolar epithelial cells through the generation of ROS. Simi- larly, Asami et al

35)

have demonstrated increased levels of 8-hydroxyguanine in leukocytes obtained from smokers to that of nonsmokers. The increased levels of cigarette smoke- mediated carcinogen-DNA in the lung tissue of smokers has been suggested to be associated with increased iron burden in lower respiratory tract.

36,37)

This suggests that the recruitment of inflammatory cells may cause oxidative DNA damage in lung cells which may be a contributing factor in the patho- genesis of lung cancer. Thus cell death may increase in parallel to cell proliferation, thereby leading to no net increase in cel- lular number. When cell death mechanisms become attenu- ated, tumor will grow and invade local structures. Thus quanti- fying cell death and cellular proliferation can provide informa- tion about the process of carcinogenesis and the response to chemoprevention treatment regime.

Indeed cigarette smoke alters chromatin remodelling and induces proinflammatory genes in rat lungs.

38)

In this seminal work, it was shown that cigarette smoke exposure was associ- ated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase and that this was concomitant with increased histone 3-phosphoacetylation, histone 4 acetyla- tion and increased DNA binding of the redox sensitive trans- cription factor NF-κB but independent of the inhibitory protein κB (IκB) degradadtion and activator protein 1 (AP-1). The association of core histone proteins with DNA is critical to the regulation of gene transcription and expression by limiting the accessibility of the genome to the transcriptional machinery, invoking the importance of histone deacetylases (HDACs).

39)

The disruption of the acetylation/

deacetylation balance is thought to lead to sustained gene

transcription of proinflammatory genes that are controlled by

AP-1, NF-κB. This would mediate the influx of

proinflammatory cells thereby creating a chronic cycle of

inflammation that can be exacerbated by cigarette smoke. Thus

AP-1, NF-κB and inhibitors of HDACs and p38 MAPK are

promising targets for cancer prevention.

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Table 1. Chemical structures of flavonoids and some examples

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Classes Structural formula Examples

ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Flavanones R=R1=H, R11=R111=OH; Naringenin

R=OH, R1=H, R11=R111=OH; Eriodyctiol R=R1=OH, R11=R111=OH; 51-OH-Eriodyctiol

Flavones R=R1=H; Apigenin

R=OH, R1=H; Luteolin R=R1=OCH3; Tricetin

Isoflavones R = H; Daidzein

R = OH; Genistein

Flavonols R=R1=H; Kaempferol

R= OH, R1=H; Quercetin R=R1=OH; Myricetin

R=OH, R1= H; (-)-Epicatechin R=R1=OH; (-)-Epigallocatechin R=OH, R1=H; (+)-Catechin R=R1=OH; (+)-Gallocatechin

Flavanols R= OH, R1= H; (+)-Epicatechin

R=R1=OH; (+)-Epigallocatechin R=OH, R1=H; (-)-Catechin R=R1=OH; (-)-Gallocatechin

ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

O

O

R"

C B R

R'

OH

R''' A

O

O

OH

C

B R

R'

OH A OH

O

O

OH OH

H R

A C

B

O

O

OH

C B R

R'

OH A OH

OH

O

OH

C B R

R'

OH A OH

OH O

OH

C B R

R'

OH A OH

OH

(7)

OXIDATIVE STRESS AND CELL SIGNALLING

ROS can lead to the activation of various other cell signalling pathway components. Examples include the extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 kinase, PI-3K/Akt, via sensitive cysteine rich domains and the sphingomyelinase-ceramide pathway, all of which lead to increased gene transcription.

40,41)

Indeed, activation of members of the MAPK family triggers the transactivation of transcrip- tion factors, such as c-Jun, activating transcription factor-2 (ATF2), cyclic AMP response element binding proteins (CREB)- binding protein (CBP) and Elk-1. This eventually results in the expression of a battery of distinct genes that can regulate pro- inflammatory, pro-apoptotic and antiproliferative responses.

Likewise, lipid peroxidation products have been shown to act as a signal for activation of transcription factors and gene expression, leading to both an inflammatory as well as a pro- tective/stress response. The induction of glutamate cysteine ligase may be an important adaptive response of the alveolar epithelium when attacked by oxidative stress and by lipid peroxidation products such as 4-hydroxy-2-nonenal.

42)

Further, the thioredoxin gene, is induced by 4-hydroxy-2-nonenal in response to lipopolysaccharide challenge in mice thereby pro- viding endotoxin tolerance.

43)

FOOD AND DIETARY COMPONENTS IN CHEMOPREVENTION STRATEGIES

Diet may influence genetic and epigenetic events associated with several cancer processes: DNA repair, carcinogenic meta- bolism, hormonal regulation, cell cycle, apoptosis and differen- tiation. Several classes of dietary compounds have been sug- gested to reduce the risk of some cancers, especially those of the gut, and there is some evidence that consumption of certain foods leads to a reduction in biomarkers of oxidative damage.

In the main, most of the extracts contain important vitamins, vitamin E, vitamin C, β-carotene, flavonoids and other poly- phenols

44∼51)

that can become bio-available upon consumption.

Flavonoids are ubiquitous in plant foods and are of different types (Table 1) namely, flavonols, flavones, isoflavones, flavo- nones, flavanol and anthocyanins. The bioactive food com- ponents are known to influence multiple biological processes, and it is clear that determining which is most instrumental in bringing about a phenotypic change is critical to the future of nutrition and health because it will assist in determining who may benefit and who may be placed at risk by intervention strategies. Dietary polyphenols have antioxidant and anti- inflammatory properties that might explain their beneficial effects.

50)

Curcumin is an active principle of the perennial herb Curcuma longa (commonly known as turmeric). Turmeric has historically been used in the orient for the treatment of many

Table 1. Continued

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Classes Structural formula Examples

ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Anthocyanidins R=OH, R1=H; Cyanidin

R=R1=OH; Delphinidin R=R1=OCH3; Malvidin R=R1=H; Pelargonidin

R=H; Peonidin R=OH; Petunidin

ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

+ OH O

A C

OH

R'

OH OH

R

+ OH O

A C

OH

OH OH

OCH3

R

(8)

ailments, particularly for inflammatory diseases. Curcumin has been shown to inhibit NF-κB expression/activation, IL-8 re- lease, cycloxygenase-2 and HO-1 expression in vitro in lung cells.

52,53)

Curcumin has multiple properties to protect against cigarette smoke-mediated oxidative stress. It acts as a radical scavenger, increases antioxidant glutathione levels by induction of glutamate cysteine ligase and as an anti-inflammatory agent through inhibition of NF-κB and IL-8 release in lung cells.

Resveratrol, a flavanoid found in red wine, is an effective inhibitor of inflammatory cytokine release from macrophages in COPD patients and in alveolar epithelial cells. The anti- inflammatory property of resveratrol may be due either to its ability to induce sirtuins and perhaps deacetylase activity or via induction of phase II detoxifying genes by an Nrf-2-dependent process.

The dietary polyphenols can restore glucocorticoid functions in response to oxidative stress imposed by cigarette smoke by upregulation of HDAC activity in the monocyte/macrophage (U937) and MonoMac6 cell lines. This has been associated with restoration of HDAC1, HDAC2 and HDAC3 levels suggesting that dietary polyphenols-mediated inhibition of pro-inflamma- tory cytokines increases formation of HDAC-p65 complex with glucocorticoid receptor hence rendering NF-κB ineffective.

The other possible mechanism of polyphenols-mediated inhibi- tion of inflammatory response is by quenching oxidants and aldehydes, and inhibiting histone deacetyltransferase activity.

Catechins present in green tea (epigallocatechin-3-gallate), in addition to theophylline, may be effective in cigarette smoke mediated oxidative stress and inflammatory response.

54)

Thus dietary polyphenols and flavonols may not only act as antio- xidant/anti-inflammatory agents but it is also possible that they may increase the efficacy of glucocorticosteroids in COPD and chronic diseases that are affected by cigarette smoke.

Result of a study conducted in Dutch cities by Tabak et al

55)

have shown that dietary intake of catechin (e.g. green tea poly- phenols, epigallocatechin gallate), flavonol (e.g. quercetin and kaempferol), and flavone (such as apigenin and luteolin) was positively associated with FEV

1

and inversely associated with chronic cough and breathlessness, but not with chronic sputum production. More importantly, single components, such as cate- chin intake were independently associated with FEV

1

and all three COPD symptoms, whereas flavonol and flavone intake was independently associated with chronic cough only. The importance of this study has been further substantiated by

Walda et al,

56)

who showed the beneficial and protective effect of fruits containing polyphenols and vitamin E intake against COPD symptoms in 20-year COPD mortality from Finnish, Italian and Dutch cohorts. These studies certainly encourage carrying out further multi-national studies to demonstrate the beneficial effects of a high intake of nutraceuticals (polyphenols/

bioflavanoids) and novel biotechnology products such as the catechin rich oligonol. Cancer involves chronic inflammatory responses. That dietary polyphenols regulate inflammatory response at the molecular level clearly point to the fact that an effective wide spectrum antioxidant therapy that has good bioavailability and potency is urgently needed to control the localized redox reactions and cellular damage in chronic inflammation. Defining if the presence of oxidative stress induced by smoking and how this could be attenuated by the administration of antioxidant compounds in food plants coupled with establishing the relationship to the presence of particular genetic polymorphism and modulation of the complex cell signalling cascades involving gene transcription remain a major future scientific challenge. This is important also for other diseases of chronic inflammation and the acute insult of stroke.

ACKNOWLEDGEMENT

Okezie I Aruoma acknowledges the Korean Ministry of Science and Technology (KMOST) for the Brain Pool Award (2004∼2005). Irfan Rahman is supported by the Environ- mental Health Sciences Center Support ES01247, and NIEHS- EHSC Pilot Project fund. Mi-Kyung Sung acknowledge the Korean Sience and Engineering Foundation (R01-2005-000- 10602-0).

REFERENCES

1) Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA.

Environmental and chemical carcinogenesis. Sem Cancer Biol 14, 473-486, 2004.

2) Church T, Pryor WA. Free radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 64, 111-126, 1985.

3) Freudenheim JL, Bonner M, Krishnan S, Ambrosome CB,

Graham S, McCann SE, Moysich KB, Bowman E, Nemoto

T, Shields PG. Diet and alcohol consumption in relation to

p53 mutations in breast tumors. Carcinogenesis 25, 931-939,

2004.

(9)

4) Aruoma OI, Halliwell B. Molecular biology of free radicals in human diseases. London, OICA International, 1998.

5) Halliwell B, Gutterdge JMC. Free radicals in biology and medicine. Oxford, University Press, 1999.

6) Aruoma OI, Bahorun T, Clement Y, Mersch-Sundermann V.

Inflammation, cellular and redox signalling mechanisms in cancer and degenerative diseases. Mut Res (in press, on line 27 July 2005).

7) Aruoma OI, Halliwell B. DNA and free radicals. Techniques, principles and applications, London, OICA International 8) Rahman I. MacNee W. Role of oxidants/antioxidants in smo-

king-induced airways diseases. Free Radical Biol Med 21, 669-681, 1996.

9) Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung disease. J

Biochem Mol Biol 36, 95-109, 2003.

10) Nakayama T, Church DF, Pryor WA. Quantitative analysis of the hydrogen peroxide formed in aqueous cigarette tar extracts. Free Radical Biol Med 7, 9-15, 1989.

11) Bouchardy C, Benhamou S, Jourenkova N, Dayer P, Hirvonen A. Metabolic genetic polymorphisms and susceptibility to lung cancer. Lung Cancer 32, 109-112, 2001.

12) Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin JM.

Genetic polymorphisms and lung cancer susceptivility; a re- view. Lung Cancer 37, 241-256, 2002.

13) Kiyohara C, Shirakawa T, Hopkin JM. Genetic polymorphism of enzymes involved xenobiotic metabolism and the risk of lung cancer. Environ Health Prev Med 7, 47-59, 2002.

14) Halliwell B, Aruoma OI. DNA damage by oxygen-derived species. Its mechanism of action and measurement in mammalian system. FEBS Lett 281, 9-19, 1991.

15) See the series of articles in the special issue: Oxidative DNA damage and its excision repair. Mut Res 531, 1-251 2003.

16) Spencer JPE, Jenner A, Chimel K, Aruoma OI, Cross CE, Wu R Halliwell B. DNA damage in respiratory tract epithelial cells: damage by gas phase cigarette smoke apparently in- volves attack by reactive nitrogen species in addition to oxygen radicals. FEBS Lett 375, 179-182, 1995.

17) Spencer JPE, Jenner A, Chimel K, Aruoma OI, Cross CE, Wu R, Halliwell B. DNA strand breakage and base modification induced by hydrogen peroxide treatment of human repiratory tract epithelial cells. FEBS Lett 374, 233-236, 1995.

18) Deiana M, Aruoma OI, Bianchi MLP, Spencer JPE, Kaur H, Halliwell B, Aeschbach R, Banni, Dessi MA, Corongiu FP.

Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol. Free Radical Biol Med 26, 762-769, 1999.

19) Mayne ST. Beta carotene, carotenoids, and disease prevention in humans. FASEB J 10, 690-701, 1996.

20) Alpha-tocopherol, Beta-Carotene Ccancer Prevention Study Group. The effect of vitamin E and β-catotene on the inci- dence of lung cancer and other cancer in male smokers. N

Engl J Med 330, 1029-1035, 1994

21) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL Jr, Valanis B, Williams JH Jr, Barnhart S, Cherniack MG, Brodkin CA, Hammar S.

Risk factors for lung cancer and for intervention effects in CARET, the beta-ccarotene and retinol efficacy trial. J Natl

Cancer Inst 88, 1550-1559, 1996.

22) Paolza P, Serini S, Nicuolo D, Boninsegna A, Torsello, Maggiano N, Ranelletti FO, Wolf FI, Calviello G, Cittadini A. β-carotene exercebates DNA oxidative dame andmodifies p53-related pathways of cell proliferation and apoptosis in cultured cells exposed to tobacco smoke condensate. Car-

cinogenesis 25, 315-1325, 2004.

23) Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Robert II LJ. Increase in circulating products of lipid peroxidation (F

2

-isoprostanes) in smokers. N Engl J Med 332, 1198-1203, 1995.

24) Basu S, Metabolism of 8-iso-prostaglandin F

. FEBS Lett 428, 32-36, 1998.

25) Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146, 3-15, 1995.

26) Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its signi- ficance in cancer and cancer therapy. Cancer 73, 2013-2026, 1994.

27) Fadeel B, Orrenius S, Zhivotovsky B. Apoptosis in human disease: a new skin for the old ceremony? Biochem Biophys Res

Commun 266, 699-717, 1999.

28) Warner HR, Hodes RJ, Pocinki K. What does cell death have to do with aging? J Am Geriat Soc 45, 1140-1146, 1997.

29) Saikumar P, Dong Z, Mikhailov V, Denton M, Weinberg JM, Venkatachalam MA. Apoptosis: definition, mechanisms, and relevance to disease. Am J Med 107, 489-506, 1999.

30) Braithwaite KL, Rabbitts PH. Multi-step evolution of lung cancer. Semin Cancer Biol 9, 255-265, 1999.

31) Pryor WA. Biological effects of cigarette smoke, wood smoke, and the smoke from plastics: the use of electron spin reso- nance. Free Rad Biol Med 13, 659-676, 1992

32) Bermudez E, Stone K, Carter KM, Pryor WA. Environmental tobacco smoke is just as damaging to DNA as mainstream smoke. Environ Health Perspect 102, 870-874, 1994.

33) Izzotti, A, Balansky R, Scatolini L, Rovida A, Flora SD.

Inhibition of N-acetylcysteine of carcinogen-DNA adducts in the tracheal epithelium of rats exposed to cigarette smoke.

Carcinogenesis 16, 669-672, 1995.

34) Leanderson P and Tagesson C. Cigarette tar promotes neutro- phil-induced DNA damage in culture lung cells. Environ Res 64, 103-111, 1994.

35) Asami S, Hirano T, Yamaguchi R, Tomioka Y, Itoh H, Kasai H. Increase of a type of oxidative DNA damage, 8-hydro- xyguanine, and its repair activity in human leukocytes by cigarette smoking. Cancer Res 56, 2546-2549, 1996.

36) Thompson AB, Bohling T, Heires A, Linder J, Rennard SI.

Lower respiratory tract iron burden is increased in association

(10)

with cigarette smoking. J Lab Clin Med 117, 494-499, 1991.

37) Philips DH, Hewer A, Martin CN, Garner RC, King MM.

Correlation of DNA adduct levels in human lung with cigarette smoking. Nature (London) 336, 790-792, 1998.

38) Marwick JA, Kirkham PA, Stevenson CS, Dnahay H, Gid- dings J, Butler K, Donaldson K, MacNee W, Rahman I.

Cigarette smoke alters chromatin remodelling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol 31, 633-642, 2004.

39) De Ruijter AJM, van Gennip AH, Caron HN, Kemp S, van Kuilenburg N. Histone deacetylases (HDACs) characterization of the classical HADC family. Biochem J 370, 737-749, 2003.

40) Gupta D, Campbell B, Derijard B, Davis RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267, 389-393, 1995.

41) Derijard B, Raingeaud J, Barret T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP-kinase signal trans- duction pathways defined by MEK and MKK isoforms. Science 267, 682-685, 1995.

42) Liu RM, Borok Z, Forman HJ. 4-Hydroxy-2-nonenal increases γ-glutamylcysteine synthetase gene expression in alveolar epithelial cells. Am J Respir Cell Mol Biol 24, 499-505, 2001.

43) Sano H, Sata T, Nanri, H, Ikeda M, Shigematsu A. Thio- redoxin is associated with endotoxin tolerance in mice. Crit

Care Med 30, 190-194, 2002.

44) Aruoma OI. Nutrition and health aspects of free radicals and antioxidants. Food Chem Toxicol 32 671-683 1994.

45) Hollman PCH, Katan MB. Dietary flavonoids: Intake, health effects and bioavailability. Food Chem Toxicol 37, 937-942, 1999.

46) Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coro- nary heart disease. Lancet 342, 1007-1011, 1993.

47) Surh YJ, Chun KS, Cha HH, Keum YS, Park KK, Lee SS.

Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation.

Mutat Res 480-481, 243-268, 2001.

48) Surh Y-J. Cancer chemoprevention with dietary phytoche- micals. Nature Rev Cancer 3, 768-780, 2003.

49) Young MR, Yang H-S, Colburn NH. Promising molecular targets for cancer prevention: AP-1, NF-κB and Pdcd4. Trend

Mol Med 9, 36-41, 2003.

50) Neergheen VS, Soobrattee MA, Bahorun T, Aruoma OI.

Characterization of the phenolic constituents in Mauritian endemic plants as determinants of their antioxidant activities in vitro. J Plant Physiol 2005 (in press)

51) Soobrattee MA, Neergheen VS, Luximon-Ramma A, Aruoma OI, Bahorun T. Phenolics as potential antioxidant therapeutic agents: mechanism and actions. Mut Res 579, 200-213, 2005.

52) Biswas SK, McClure D, Jimenez LA, Megson IL, Rahman I.

Curcumin induces glutathione biosynthesis and inhibits NF-κB activation and interleukin-8 release in alveolar epithelial cells:

mechanism of free radical scavenging activity. Antioxid Redox Signal 7, 32-41, 2005.

53) Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha ki- nase in human lung epithelial cells: correlation with sup- pression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 24, 1269-1279, 2003.

54) Schwartz JL, Baker V, Larious E, Chung FL. Molecular and cellular effects of green tea on oral cells of smokers: a pilot study. Mol Nutr Food Res 49, 43-51, 2005.

55) Tabak C, Ilja C, Arts CW, Smit HA, Heederik D, Kromhout D. Chronic obstructive pulmonary disease and intake of cate- chins, flavonols, and flavones: the MORGEN Study. Am J

Respir Crit Care Med 164, 61-64, 2001.

56) Walda IC, Tabak C, Smit HA, Rasanen L, Fidanza F, Menotti

A, Nissinen A, Feskens EJM, Kromhout D. Diet and 20-year

chronic obstructive pulmonary disease mortality in middle-

aged men from three European countries. Eur J Clin Nutr 56,

638-643, 2002.

수치

Fig. 2. Oxidative stress-mediated lung injury and inflammation  lead-ing to lung cancer.
Fig. 3. Exposure of cells to cigarette produce significant changes in DNA base products
Fig. 4. Effect of hydrogen peroxide on DNA in human respiratory tract epithelial cells
Table 1. Chemical structures of flavonoids and some examples

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