Competing Roles of Aldo-Keto Reductase 1A1 and Cytochrome P4501B1 in Benzo[<i>a</i>]pyrene-7,8-diol Activation in Human Bronchoalveolar H358 Cells:  Role of AKRs in P4501B1 Induction

Jiang, Hao; Vudathala, Daljit; Blair, Ian A.; Penning, T.M.

doi:10.1021/tx0502488

Cited by 42 publications

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“…Our recent metabolism studies showed that the P450 1A1/1B1 and the AKR pathways can effectively compete for B[a]P-7,8-transdihydrodiol activation in AKR1A1 stably transfected H358 cells (19). In the present work, we exploited A549 cells because they have high constitutive expression of AKR1C1-1C3 isoforms (20).…”

Section: Discussionmentioning

confidence: 99%

“…Jiang et al (18,19) In the A549 cell extracts B[a]P-7,8-trans-dihydrodiol was converted to B[a]P-7,8-dione, which was trapped with ␤-mercaptoethanol in situ as a thio-ether conjugate. The conjugate was identified by coelution with an authentic synthetic standard that was characterized by LC-atmospheric pressure chemical ionization (APCI)/MS, as described ( Fig.…”

Section: Anti-b[a]pde}mentioning

confidence: 99%

“…The conjugate was identified by coelution with an authentic synthetic standard that was characterized by LC-atmospheric pressure chemical ionization (APCI)/MS, as described ( Fig. 1 A and C) (18,19). The formation of B[a]P-7,8-dione was maximal at the (Fig.…”

Section: Anti-b[a]pde}mentioning

confidence: 99%

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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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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%

Section: Anti-b[a]pde}mentioning

confidence: 99%

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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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“…27, 28). The AKR-generated B[a]P-7,8-dione is a ligand for the aryl hydrocarbon receptor and will induce CYP1A1 and CYP1B1 still further (29,30). Moreover, the B[a]P-7,8-dione and the reactive oxygen species it generates induce AKR1C1-AKR1C3 genes via their antioxidant response elements (31,32).…”

Section: Significance For Cancer Etiologymentioning

confidence: 99%

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

Penning

Lerman²

2008

Cancer Prevention Research

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“…The competing roles of P4501A1/1B1 and AKR1A1 in the metabolic activation of B[a]P-7,8-dihydrodiol has been examined in H358 cells manipulated to express either enzyme system. We found that AKR1A1 had a dual effect: it oxidized (-)-B[a]P-7,8-dihydrodiol to B[a]P-7,8-dione, but B[a]P-7,8-dione also acted as a ligand for the AhR leading to the induction of the P4501B1 gene (47). Thus, the P450 pathway generates metabolites that induce the AKR pathway and vice versa.…”

Section: Introductionmentioning

confidence: 97%

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

Jiang

Gelhaus

Mangal

et al. 2007

Chem. Res. Toxicol.

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Benzo [a]pyrene (B[a]P), a representative polycyclic aromatic hydrocarbon (PAH), is metabolically activated by three enzymatic pathways; by peroxidases (e.g. cytochrome P450-peroxidase) to yield radical cations; by P4501A1/1B1 monoxygenation plus epoxide hydrolase to yield diol-epoxides; and by P4501A1/1B1 monoxygenation, epoxide hydrolase plus aldo-keto reductases (AKRs) to yield o-quinones. In humans, a major exposure site for environmental and tobacco smoke PAH is the lung, however, the profile of B[a]P metabolites formed at this site has not been well characterized. In this study, human bronchoalveolar H358 cells were exposed to B[a]P, and metabolites generated by peroxidase (B[a]P-1,6-and B[a]P-3,6-diones), from cytochrome P4501A1/1B1 monooxygenation (3-hydroxyl-B[a]P, B[a]P-7,8-and 9,10-trans-dihydrodiols, and B[a]P -r-7,t-8,t-9,c-10-tetrahydrotetrol (B[a]P -tetrol-1)), and from AKRs (B[a]P-7,8-dione) were detected and quantified by RP-HPLC-with in line photo-diode array and radiometric detection, and identified by LC-MS. Progress curves showed a lag-phase in the formation of 3-hydroxy-B[a]P, B[a]P-7,8-transdihydrodiol, B[a]P-tetraol-1 and B[a]P-7,8-dione over 24 h. Northern blot analysis showed that B [a]P induced P4501B1 and AKR1C isoforms in H358 cells in a time-dependent manner providing an explanation for the lag-phase. Pretreatment of H358 cells with 10 nM 2,3,7,8-tetrachlorodibenzop-dioxin, (TCDD) eliminated this lag-phase, but did not alter the levels of the individual metabolites observed, suggesting that both B[a]P and TCDD induction ultimately yield the same B[a]P-metabolic profile. The one exception was B[a]P-3,6-dione which was formed without a lag-phase in the absence and presence of TCDD, suggesting that the peroxidase responsible for its formation was neither P4501A1 nor 1B1. Candidate peroxidases that remain include PGH synthases and uninduced P450 isoforms. This study shows that the P4501A1/1B1 and AKR pathways are inducible in human lung cells and that the peroxidase pathway was not. It also provides evidence that each of the pathways of PAH-activation yield their distinctive metabolites in H358 human lung cells and that each pathway may contribute to the carcinogenic process.

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Competing Roles of Aldo-Keto Reductase 1A1 and Cytochrome P4501B1 in Benzo[a]pyrene-7,8-diol Activation in Human Bronchoalveolar H358 Cells: Role of AKRs in P4501B1 Induction

Cited by 42 publications

References 44 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

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

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