Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans.
A useful approach for studies on the mechanisms of genetic variation in cancer susceptibility is to use intermediary biochemical endpoints with mechanistic relevance to the genes under study. We examined the effects of individual genotype at seven metabolic gene loci on a marker of oxidative DNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine, in people exposed to polycyclic aromatic hydrocarbons (PAH) from three Central European cities. The GSTT1 homozygous deletion variant was associated with a significant protective effect for exposure to total PAHs and to eight specific PAHs, although the magnitude and significance of the effect varied among these compounds. Categorical sensitivity analysis was used to determine that the frequency of the GSTT1 deletion was significantly higher in people who proved to be more resistant to the DNA damaging effects of PAH exposure than in people who were the most sensitive. There is a growing literature on the protective effect of GSTT1 deletion in both disease and intermediary endpoints related to environmental carcinogenesis. The mechanism for this effect might be related to specific PAH substrate specificities, or could be related to other functions of GSTT1 gene in oxidative stress induced damage pathways.
Garte
Seymour
S
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. sjgarte@upmc.edu
Taioli
Emanuela
E
Popov
Todor
T
Kalina
Ivan
I
Sram
Radim
R
Farmer
Peter
P
D004249:DNA Damage; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D011083:Polycyclic Compounds / Q000633:toxicity*
D011083:Polycyclic Compounds; D005982:Glutathione Transferase; C495790:glutathione transferase T1-1, human