| Aldo-keto reductase- and cytochrome P450-dependent formation of benzo[a]pyrene-derived DNA adducts in human bronchoalveolar cells. | |
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MedLine Citation:
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PMID: 17295519 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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There is substantial evidence to suggest that polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) induce lung cancer through metabolic activation. As part of a program to delineate the routes of PAH activation, we have examined DNA adducts that are formed in human lung cells. A stable isotope dilution liquid chromatography/multiple reaction monitoring mass spectrometry method was used to quantify eight anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-B[a]P (B[a]PDE)-derived DNA adducts in four H358 human bronchoalveolar cell lines with different phenotypes. In P450 1A1/P450 1B1-induced H358 cells exposed to (+/-)-B[a]P-7,8-dihydro-7,8-diol (B[a]P-7,8-dihydrodiol), (+)-anti-trans-B[a]PDE-N2-2'-deoxyguanosine [(+)-anti-trans-B[a]PDE-N2-dGuo] was the major DNA adduct, and it formed with no lag phase. In AKR1A1-transfected H358 cells, (+)-anti-trans-B[a]PDE-N2-dGuo was also the major adduct with a 3 h lag phase before significant adduct formation was detected. In AKR1A1-transfected H358 cells with induced P450 1A1/P450 1B1, (+)-anti-trans-B[a]PDE-N2-dGuo was formed with no lag phase in amounts similar to those in the H358 cells with up-regulated P450 1A1/P450 1B1. Surprisingly, the greatest amount of (+)-anti-trans-B[a]PDE-N2-dGuo was formed in the control H358 cells. Furthermore, (+)-anti-trans-B[a]PDE-N2-dGuo formation was 2-fold higher in (-)-B[a]P-7,8-dihydrodiol-exposed H358 cells when compared with (+/-)-B[a]P-7,8-dihydrodiol-exposed cells. The P450 1A1/1B1 inhibitor 2,4,3',5'-tetramethoxystilbene did not attenuate DNA adduct formation in the control H358 cells, suggesting that another P450 was responsible. These data raise the intriguing possibility that P450 1A1/P450 1B1 and AKR1A1 may be protective against (+)-B[a]PDE-mediated DNA damage. |
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Authors:
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Qian Ruan; Stacy L Gelhaus; Trevor M Penning; Ronald G Harvey; Ian A Blair |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-02-13 |
Journal Detail:
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Title: Chemical research in toxicology Volume: 20 ISSN: 0893-228X ISO Abbreviation: Chem. Res. Toxicol. Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-03-19 Completed Date: 2007-05-21 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 8807448 Medline TA: Chem Res Toxicol Country: United States |
Other Details:
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Languages: eng Pagination: 424-31 Citation Subset: IM |
Affiliation:
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Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol Oxidoreductases
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metabolism* Aldehyde Reductase / metabolism* Benzo(a)pyrene / metabolism*, toxicity* Bronchoalveolar Lavage Fluid / cytology* Cytochrome P-450 Enzyme System / metabolism* DNA Adducts / drug effects*, isolation & purification Humans Hydrolysis Spectrophotometry, Ultraviolet Stereoisomerism Teratogens / toxicity Tetrachlorodibenzodioxin / toxicity Transfection |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA92537/CA/NCI NIH HHS; P30 ES013508/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Adducts; 0/Teratogens; 1746-01-6/Tetrachlorodibenzodioxin; 50-32-8/Benzo(a)pyrene; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.1.-/Alcohol Oxidoreductases; EC 1.1.1.21/Aldehyde Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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