Effects of metabolic genotypes on intermediary biomarkers in subjects exposed to PAHS: results from the EXPAH study.
Data from the EXPAH project on PAH exposure and intermediary biomarkers were analyzed with respect to individual genotypes at seven metabolic gene loci. The GSTM1 null allele was associated with significantly higher levels of two biomarkers, malondialdehyde-2'-deoxyguanosine and benzo[a]pyrene DNA adducts in the total population from three Central and Eastern European countries. The CYP1B1 Leu/Val variant demonstrated effects on both markers of oxidative DNA damage in opposite directions, producing a higher level of M(1)dG with a trend from wild type (Leu/Leu) to heterozygotes to homozygous (Val/Val) variants, whereas the effects of these variants were reversed for 8-oxodG. Cluster Analysis was used to group composite genotypes in order to determine if combined genotypes of multiple loci could explain some of the variation seen with the biomarkers, expressed per unit of exposure, referred to as a sensitivity index. This analysis revealed two closely related genotypes each involving four of the loci (GSTM1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1 and GSTT1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1.) that conferred significant resistance to the DNA damaging effects of benzo[a]pyrene, measured as the level of a benzo[a]pyrene-like adduct per unit of benzo[a]pyrene exposed.
Garte
Seymour
S
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. sjgarte@yahoo.com
Taioli
Emanuela
E
Raimondi
Sara
S
Paracchini
Valentina
V
Binkova
Blanka
B
Sram
Radim J
RJ
Kalina
Ivan
I
Popov
Todor A
TA
Singh
Rajinder
R
Farmer
Peter B
PB
D000393:Air Pollutants / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001564:Benzo(a)pyrene / Q000633:toxicity; D015415:Biomarkers; D002274:Carcinogens, Environmental / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D004784:Environmental Monitoring; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*
D000393:Air Pollutants; D001189:Aryl Hydrocarbon Hydroxylases; D001564:Benzo(a)pyrene; D015415:Biomarkers; D002274:Carcinogens, Environmental; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D011084:Polycyclic Aromatic Hydrocarbons; C585496:CYP1B1 protein, human; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human