Formation of 8-Oxo-7,8-dihydro-2‘-deoxyguanosine (8-Oxo-dGuo) by PAH <i>o</i>-Quinones:  Involvement of Reactive Oxygen Species and Copper(II)/Copper(I) Redox Cycling

Park, Jong-Heum; Gopishetty, Sridhar; Szewczuk, Lawrence M.; Troxel, Andrea B.; Harvey, Ronald G.; Penning, T.M.

doi:10.1021/tx050001a

Cited by 75 publications

(89 citation statements)

References 48 publications

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“…PAH o-quinones produced by AKRs cause oxidative DNA damage in the form of 8-oxo-dGuo in vitro (30). However, whether 8-oxo-dGuo could be detected reliably as a result of PAH activation by AKRs in intact cells was unknown.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans -dihydrodiol activation in human lung A549 cells

Park

Mangal

Tacka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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108

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8-oxo-dGuo ͉ DNA strand breaks ͉ tobacco carcinogens ͉ reactive oxygen species P olycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, which are produced as a result of fossil-fuel combustion and are found in car exhaust and charbroiled and smoked foods (1, 2). They are also present as mixtures in tobacco smoke and are implicated in the causation of human lung cancer (3). To exert their carcinogenic effects, PAHs must be metabolically activated to DNA-damaging agents that will result in the signature mutations in lung cancer. These mutations are G-to-T transversions that either activate the K-ras protooncogene at the 12th and 61st codon (4) or inactivate the p53 tumor suppressor gene at hot spots in its DNA binding domain (5).Using benzo[a]pyrene (B[a]P) as a representative PAH, three pathways of activation have been proposed that lead to these mutations. The first pathway involves the formation of (ϩ)-anti-7␣,8␤-dihydroxy-9␣,10␤-epoxy-7,8,9,10-tetrahydroB[a]P {(Ϯ)- anti-B[a]PDE}.In this pathway there is sequential monoxygenation catalyzed by cytochrome P450 (P450) 1A1/1B1 and hydration to form 7␣,8␤-dihydroxy-7,8-dihydroxy-B[a]P, which undergoes a secondary monoxygenation to form (ϩ)-anti-B[a]PDE (6). This diol-epoxide forms stable (ϩ)-anti-trans-B[a]PDE-N 2 -2Ј-deoxyguanosine (dGuo) adducts, which via trans-lesional bypass DNA polymerases, yield G-to-T transversions (7).The second pathway involves metabolic activation by P450 peroxidases to yield radical cations (8), which can form depurinating adducts that lead to abasic sites. Apurinic/apyrimdinic (AP) sites, if not repaired, can give rise to G-to-T transversions (9). However, it is unlikely that radical cations are sufficiently long-lived to damage DNA in intact cells.The third pathway of PAH activation is the NAD(P ϩ )-dependent oxidation of PAH-trans-dihydrodiols to PAH oquinones catalyzed by dihydrodiol dehydrogenase members of the aldo-keto reductase (AKR) superfamily (10). AKRs divert PAH trans-dihydrodiols to form ketols that spontaneously rearrange to catechols (Scheme 1). The catechols undergo two one-electron oxidation events to produce the corresponding redox-active and electrophilic o-quinones. PAH o-quinones can form stable and depurinating DNA adducts in vitro (11,12), and these adducts may provide a route to G-to-T transversion mutations.In the presence of NAD(P)H, PAH o-quinones also undergo nonenzymatic reduction back to catechols. This event establishes futile redox cycles, which amplify the generation of reactive oxygen species (ROS) at the expense of NADPH and may lead to a prooxidant cellular state. Because a prooxidant state has been associated with tumor initiation and promotion (13), the AKR pathway of PAH activation is attractive in that it could explain how PAHs act as complete carcinogens. In addition, ROS may cause oxidative DNA damage such as 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxo-dGuo) lesions, which can lead to G-to-T transversions (14). Amplification of ROS by catechol-oquinone interconversion has...

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Section: Discussionmentioning

confidence: 99%

Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans -dihydrodiol activation in human lung A549 cells

Park

Mangal

Tacka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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108

106

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“…The electrophilic and redox active o-quinones can form a spectrum of DNA-adducts and evidence exists for stable bulky adducts formed by 1,4-Michael addition (which subsequently hydrate and cyclize) [68][69][70], the formation of depurinating DNA-adducts [71] , and the formation of 8-oxo-dGuo [72]. In vitro measurements of DNA-adduct formation suggest that the prominent lesions are those that result from oxidative damage of DNA [73].…”

Section: Poylcyclic Aromatic Hydrocarbonsmentioning

confidence: 99%

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Penning

Drury

2007

Archives of Biochemistry and Biophysics

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Aldo-Keto Reductases (AKRs) are a superfamily of NAD(P)H linked oxidoreductases that are generally monomeric 34-37 kDa proteins present in all phyla. The superfamily consists of 15 families, which contains 151 members (www.med.upenn.edu/akr). Thirteen human AKRs exist that use endogenous substrates (sugar and lipid aldehydes, prostaglandins, retinals and steroid hormones), and in many instances they regulate nuclear receptor signaling. Exogenous substrates include metabolites implicated in chemical carcinogenesis: NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), polycyclic aromatic hydrocarbon trans-dihydrodiols, and aflatoxin dialdehyde. Promoter analysis of the human genes identifies common elements involved in their regulation which include osmotic response elements, antioxidant response elements, xenobiotic response elements, AP-1 sites and steroid response elements. The human AKRs are highly polymorphic, and in some instances single nucleotide polymorphisms (SNPs) of high penetrance exist. This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis.

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“…3,8) There is growing evidence that ROS have adverse effects on DNA and essential macromolecules. [8][9][10][11] Kumagai et al demonstrated that 9,10-phenanthrenequinone (9,10-PQ) is redox-active which can catalyze the transfer of electrons from dithiol to oxygen, generating superoxide. The consumption rate of thiol groups was proportional to the concentration of the catalytically active redox-active species in the sample.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress More Strongly Induced by ortho- Than para-quinoid Polycyclic Aromatic Hydrocarbons in A549 Cells

Motoyama

Bekki

Chung

et al. 2009

JOURNAL OF HEALTH SCIENCE

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The effect of four ortho-quinoid polycyclic aromatic hydrocarbons (PAHs) and seven paraquinoid PAHs on the viability of A549 cells were examined. The ortho-quinoid PAHs [1,2-naphthoquinone (1,2-NQ), 9,10-phenanthrenquinone (9,10-PQ), 5,6-chrysenequinone (5,6-CQ), and benzo[c]phenanthrene-5,6-quinone (B[c]P-5,6-Q)] overproduced hydrogen peroxide (H 2 O 2 ) without being consumed themselves. These ortho-quinoid had strong cytotoxic effects except for 1,2-NQ, since of its tendency to covalently bind to thiol groups. The cytotoxicity appears to be due to the overproduction of H 2 O 2 by ortho-quinoid PAHs in a redox cycle coupled with the consumption of thiol group. In contrast, the paraquinoid PAHs were not as strong cytotoxic and did not produce H 2 O 2 .

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Formation of 8-Oxo-7,8-dihydro-2‘-deoxyguanosine (8-Oxo-dGuo) by PAH o-Quinones: Involvement of Reactive Oxygen Species and Copper(II)/Copper(I) Redox Cycling

Cited by 75 publications

References 48 publications

Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans -dihydrodiol activation in human lung A549 cells

Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans -dihydrodiol activation in human lung A549 cells

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Oxidative Stress More Strongly Induced by ortho- Than para-quinoid Polycyclic Aromatic Hydrocarbons in A549 Cells

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