Aromatic DNA adducts and polymorphisms in metabolic genes in healthy adults: findings from the EPIC-Spain cohort.
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 (32)P-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(-9)adducts, 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.
Agudo
Antonio
A
Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain. a.agudo@iconcologia.net
Peluso
Marco
M
Sala
Núria
N
Capellá
Gabriel
G
Munnia
Armelle
A
Piro
Sara
S
Marín
Fátima
F
Ibáñez
Raquel
R
Amiano
Pilar
P
Tormo
M José
MJ
Ardanaz
Eva
E
Barricarte
Aurelio
A
Chirlaque
M Dolores
MD
Dorronsoro
Miren
M
Larrañaga
Nerea
N
Martínez
Carmen
C
Navarro
Carmen
C
Quirós
J Ramón
JR
Sánchez
M José
MJ
González
Carlos A
CA
D000107:Acetylation; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D018736:DNA Adducts / Q000097:blood* / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D011110:Polymorphism, Genetic
D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human