Document Detail

Aldo-keto reductase- and cytochrome P450-dependent formation of benzo[a]pyrene-derived DNA adducts in human bronchoalveolar cells.
MedLine Citation:
PMID:  17295519     Owner:  NLM     Status:  MEDLINE    
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.
Qian Ruan; Stacy L Gelhaus; Trevor M Penning; Ronald G Harvey; Ian A Blair
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-02-13
Journal Detail:
Title:  Chemical research in toxicology     Volume:  20     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-19     Completed Date:  2007-05-21     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  424-31     Citation Subset:  IM    
Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
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MeSH Terms
Alcohol Oxidoreductases / 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
Spectrophotometry, Ultraviolet
Teratogens / toxicity
Tetrachlorodibenzodioxin / toxicity
Grant Support
Reg. No./Substance:
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 Reductase

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