Competing Roles of Cytochrome P450 1A1/1B1 and Aldo−Keto Reductase 1A1 in the Metabolic Activation of (±)-7,8-Dihydroxy-7,8-dihydro-benzo[<i>a</i>]pyrene in Human Bronchoalveolar Cell Extracts

Jiang, Hao; Shen, Yu-Min; Quinn, and Amy M.; Penning, T.M.

doi:10.1021/tx0497245

Cited by 60 publications

(49 citation statements)

References 44 publications

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“…Further, the metabolism of PAHs induces DNA damage and carcinogenesis which could be modulated by genetic variation (Shimizu et al, 2000;Jiang et al, 2005;Ramadoss et al, 2005;Chen et al, 2006). In this study, significant difference (p=0.02, 95%CI, 0.70-15.86) was observed in the R273G mutation in p53 exon 8 for the genetic polymorphisms of Lys/Arg for AhR.…”

Section: 2699 Impact Of Ahr Cyp1a1 Gstm1 Snps On Tp53 R273g Mutatimentioning

confidence: 52%

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

Gao

Li²,

Xue³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Section: 2699 Impact Of Ahr Cyp1a1 Gstm1 Snps On Tp53 R273g Mutatimentioning

confidence: 52%

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

Gao

Li²,

Xue³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…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%

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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“…After binding with benzo(a)pyrene, AhR translocates into the nucleus to interact with xenobiotic responsive elements, resulting in the up-regulation of phase I and II enzymes, such as cytochrome P450 and glutathione S-transferases, which are also involved in the metabolism of PAHs. It is thought that it is DNA damage, caused by reactive oxygen species formed during the metabolism of PAHs, that plays a role in PAH-induced carcinogenesis (6)(7)(8). Furthermore, the DNA damage caused by PAHs in coke-oven workers could be detected in their peripheral primary lymphocytes using the alkaline comet assay (9,10), whereas PAH-induced carcinogenesis could be modulated by genetic variation (11,12).…”

Section: Introductionmentioning

confidence: 99%

Association of Polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 Genes with Levels of DNA Damage in Peripheral Blood Lymphocytes among Coke-Oven Workers

Chen

Bai

Yuan

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Accumulating evidence has shown that both DNA damage caused by the metabolites of polycyclic aromatic hydrocarbons (PAH) and genetic polymorphisms in PAH-metabolic genes contribute to individual susceptibility to PAH-induced carcinogenesis. However, the functional relevance of genetic polymorphisms in PAH-metabolic genes in exposed individuals is still unclear. In this study of 240 coke-oven workers (the exposed group) and 123 non -coke-oven workers (the control group), we genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and GSTT1 genes by PCR methods, and determined the levels of DNA damage in peripheral blood lymphocytes using the alkaline comet assay. We found that the ln-transformed Olive tail moment (Olive TM) values in the exposed group were significantly higher than those in the control group (P < 0.001). Furthermore, in the exposed group, the Olive TM values in subjects with the AhR Lys 554 variant genotype were higher than those with the AhR Arg 554 /Arg 554 genotype (P = 0.021). Similarly, the Olive TM values in the non -coke-oven workers with the CYP1A1 MspI CC + CT genotype were lower than the values of those with the CYP1A1 MspI TT genotype (P = 0.005). However, these differences were not evident for GSTM1 and GSTT1. These results suggested that the polymorphism of AhR might modulate the effects of PAHs in the exposed group; however, the underlying molecular mechanisms by which this polymorphism may have affected the levels of PAH-induced DNA damage warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1703 -7)

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Competing Roles of Cytochrome P450 1A1/1B1 and Aldo−Keto Reductase 1A1 in the Metabolic Activation of (±)-7,8-Dihydroxy-7,8-dihydro-benzo[a]pyrene in Human Bronchoalveolar Cell Extracts

Cited by 60 publications

References 44 publications

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

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

Association of Polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 Genes with Levels of DNA Damage in Peripheral Blood Lymphocytes among Coke-Oven Workers

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