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Benzo(a)pyrene Diolepoxide (BPDE)-DNA Adduct Levels in Leukocytes of Smokers in Relation to Polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH

¹ Department of Pharmacology, University of Florence, Florence, Italy; ² Blood Transfusion Unit, Arezzo Hospital, Arezzo, Italy; and ³ Department of Public Health, University of Florence, Florence, Italy

Requests for reprints: Maura Lodovici, Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Phone: 39-55-4271321; Fax: 39-55-4271280. E-mail: maura.lodovici{at}unifi.it

Benzo(a)pyrene [B(a)P] diolepoxide (BPDE)-DNA adducts were measured in the leukocytes of 41 healthy smokers using high-performance liquid chromatography coupled with a fluorimetric detector. The correlation between exposure to B(a)P through smoking and BPDE-DNA adduct levels was poor (r = 0.31), although subjects in the high exposure group [B(a)P > 50 ng/d] had a slightly higher level of adducts compared with the less exposed group (mean ± SE, 1.70 ± 0.3 versus 1.09 ± 0.1; P = 0.057). We studied the effect on BPDE-DNA adducts of individual variations in genes controlling B(a)P metabolism, classifying subjects in "low-risk" and "high-risk" genotypes for smoking-related B(a)P DNA damage. The high-risk group included subjects characterized by a combination of increased B(a)P activation [cytochrome P450 1A1 (CYP1A1) MspI and/or exon 7 Ile⁴⁶²Val allele variants and microsomal epoxide hydrolase (mEH) fast activity] and decreased deactivation ability [presence of glutathione S-transferase M1 (GSTM1) null allele and wild-type glutathione S-transferase P1 (GSTP1)]. The low-risk group included smokers with lower B(a)P activation (wild-type CYP1A1, low or intermediate mEH activity) and higher deactivation capacity (active GSTM1, GSTP1 Ile¹⁰⁵Val allele). Subjects in the low-risk group had lower levels of BPDE-DNA adducts compared with subjects in the high-risk genotype group; this difference was significant using two markers (CYP1A1 and GSTM1, median ± SD, 0.77 ± 1.16 versus 1.89 ± 0.39; P = 0.03) or three markers (CYP1A1, GSTM1, and GSTP1, median ± SD, 0.66 ± 0.93 versus 1.43 ± 1.17; P = 0.013). The discrimination between groups was reduced when including mEH as an additional marker (P = 0.085). In conclusion, CYP1A1, GSTM1, and GSTP1 genotyping seems to be a risk predictor of BPDE-DNA adduct formation in leukocytes.

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