Benzo(a)pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH.
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.
Lodovici
Maura
M
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. maura.lodovici@unifi.it
Luceri
Cristina
C
Guglielmi
Francesco
F
Bacci
Chiara
C
Akpan
Victor
V
Fonnesu
Maria Luisa
ML
Boddi
Vieri
V
Dolara
Piero
P
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D015331:Cohort Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005819:Genetic Markers; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects* / Q000097:blood; D018709:Statistics, Nonparametric
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019363:Cytochrome P-450 CYP1A1; D018736:DNA Adducts; D005819:Genetic Markers; D005982:Glutathione Transferase; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA