title: Associations between smoking, polymorphisms in polycyclic aromatic hydrocarbon (PAH) metabolism and conjugation genes and PAH-DNA adducts in prostate tumors differ by race.
abstract: Polycyclic aromatic hydrocarbon (PAH)-DNA adducts may induce mutations that contribute to carcinogenesis. We evaluated potential associations between smoking and polymorphisms in PAH metabolism [CYP1A1 Ile 462Val, CYP1B1 Ala 119Ser and Leu 432Val, microsomal epoxide hydrolase (mEH) Tyr 113His and His139Arg, CYP3A4 A(-392)G] and conjugation [glutathione S-transferase (GST) M1 null deletion, GSTP1 Ile 105Val] genes and PAH-DNA adduct levels (measured by immunohistochemistry) in tumor and nontumor prostate cells in 400 prostate cancer cases. Although no statistically significant associations were observed in the total sample, stratification by ethnicity revealed that Caucasian ever smokers compared with nonsmokers had higher adduct levels in tumor cells (mean staining intensity in absorbance units +/- SE, 0.1748 +/- 0.0052 versus 0.1507 +/- 0.0070; P = 0.006), and Caucasians carrying two mEH 139Arg compared with two 139His alleles had lower adducts in tumor (0.1320 +/- 0.0129 versus 0.1714 +/- 0.0059; P = 0.006) and nontumor (0.1856 +/- 0.0184 versus 0.2291 +/- 0.0085; P = 0.03) cells. African Americans with two CYP1B1 432Val compared with two 432Ile alleles had lower adducts in tumor cells (0.1600 +/- 0.0060 versus 0.1970 +/- 0.0153; P = 0.03). After adjusting for smoking status, carrying the putative "high-risk" genotype combination, the faster metabolism of PAH-epoxides to PAH-diol-epoxides (CYP1B1 432Val/Val and mEH 139Arg/Arg) with lower PAH-diol-epoxide conjugation (GSTP1 (105)Ile/Ile), was associated with increased adducts only in Caucasian nontumor cells (0.2363 +/- 0.0132 versus 0.1920 +/- 0.0157; P= 0.05). We present evidence, for the first time in human prostate that the association between smoking and PAH-DNA adducts differs by race and is modified by common genetic variants.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Nora L
authors.initials: NL
authors.lastname: Nock
authors.forename: Deliang
authors.initials: D
authors.lastname: Tang
authors.forename: Andrew
authors.initials: A
authors.lastname: Rundle
authors.forename: Christine
authors.initials: C
authors.lastname: Neslund-Dudas
authors.forename: Adnan T
authors.initials: AT
authors.lastname: Savera
authors.forename: Cathryn H
authors.initials: CH
authors.lastname: Bock
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.forename: Allison
authors.initials: A
authors.lastname: Koprowski
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Mitrache
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D001741:Black or African American / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000235:genetics; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D044469:Racial Groups / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D044465:White People / Q000235:genetics
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D018736:DNA Adducts; D004851:Epoxide Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D011084:Polycyclic Aromatic Hydrocarbons; C585496:CYP1B1 protein, human; C510163:CYP3A4 protein, human