Carcinogenesis Advance Access originally published online on March 23, 2009
Carcinogenesis 2009 30(6):968-976; doi:10.1093/carcin/bgp062
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Aromatic DNA adducts and polymorphisms in metabolic genes in healthy adults: findings from the EPIC-Spain cohort
1 Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), IDIBELL, Avenue Gran Via s/n km 2.7, 08907 L'Hospitalet de Llobregat, Spain
2 Cancer Risk Factor Branch, Molecular Biology Laboratory, CSPO-Scientific Institute of Tuscany Region, 50135 Florence, Italy
3 Translational Research Laboratory, Catalan Institute of Oncology (ICO), IDIBELL, Avenue Gran Via, 199-203, 08907 L'Hospitalet de Llobregat, Spain
4 Dirección de Salud de Guipúzcoa, 20013 San Sebastian, Spain
5 CIBER Epidemiología y Salud Pública (CIBERESP), Spain
6 Consejería de Sanidad y Consumo, 3008 Murcia, Spain
7 Instituto de Salud Pública de Navarra, 31003 Pamplona, Spain
8 Escuela Andaluza de Salud Pública, 18080 Granada, Spain
9 Consejería de Sanidad y Servicios Sociales de Asturias, 33001 Oviedo, Spain
* To whom correspondence should be addressed. Tel: +34 93 2607401; Fax: +34 93 2607787; Email: a.agudo{at}iconcologia.net
Aromatic compounds such as polycyclic aromatic hydrocarbons, arylamines and heterocyclic amines require metabolic activation to form metabolites able to bind to DNA, a process mediated by polymorphic enzymes. We measured aromatic DNA adducts in white blood cells by the 32P-post-labelling assay in a sample of 296 healthy adults (147 men and 149 women) from five regions of Spain. We also analyzed functional polymorphisms in the metabolic genes CYP1A1, CYP1A2, EPHX1, GSTM1, GSTT1, NAT2 and SULT1A1. A significant increased level of DNA aromatic adducts was found related to the fast oxidation–hydrolysis phenotype defined by the polymorphism I462V in CYP1A1, the allele A in IVS1–154C>A of CYP1A2 and the combination Tyrosine–Arginine for Y113H and H139R of EPHX1. Geometric means (adducts per 10–9 normal nucleotides) were 2.17, 4.04 and 6.30 for slow, normal and fast phenotypes, respectively (P-trend = 0.01). Slow acetylation by NAT2 was associated with a significant decrease in adduct level; subjects with slow alleles *5A and *7A/B had in average 1.56 x 10–9adducts, as compared with 5.60 for those with normal NAT2 activity (P-value = 0.01). No association was seen with polymorphisms of other metabolic genes such as GSTM1, GSTT1 or SULT1A1. We concluded that the metabolic pathways of oxidation, hydrolysis and acetylation are relevant to the formation of bulky DNA adducts. This could suggest a potential involvement of aromatic compounds in the formation of such adducts; however, given lack of specificity of the post-labeling assay, a firm conclusion cannot be drawn.
Abbreviations: AA, aromatic amine; BaP, benzo(a)pyrene; CI, confidence interval; CYP, cytochrome P450; EPHX, epoxide hydrolase; GST, glutathione S-transferases; HA, heterocyclic amine; HWE, Hardy–Weinberg equilibrium; LD, linkage disequilibrium; NAT, N-acetyl-transferase; PAH, polycyclic aromatic hydrocarbon; SNP, Single-nucleotide polymorphism; SULT, sulphotransferase; WBC, white blood cell
Received December 28, 2007; revised May 27, 2008; accepted May 29, 2008.
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