Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype.
Reduced glutathione (GSH) plays a critical role as an intracellular defense system providing detoxification of a broad spectrum of reactive species and their excretion as water-soluble conjugates. Conjugation of GSH with electrophiles is catalyzed by GSH S-transferases (GST), which constitute a broad family of phase II isoenzymes. Two of the GST encoding genes, GSTM1 (mu) and GSTT1 (theta), have a null genotype due to their homozygous deletion that results in lack of active protein. Polymorphisms within GSTT1 and especially GSTM1 have often been associated with cancer in various organs as well as with elevated levels of DNA adducts in various cell types. We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions. Here we provide evidence that levels of adducts to SMC DNA from atherosclerotic lesions are consistently increased in individuals having the null GSTM1 genotype, whereas no association was established with the GSTT1 polymorphism. The influence of GSTM1 deletion was better expressed in never-smokers and ex-smokers than in current smokers. These findings bear relevance to the epidemiology of atherosclerosis and suggest that metabolic polymorphisms may contribute to the interindividual variability in susceptibility not only to carcinogens, but also to DNA binding atherogens.
Izzotti
A
A
Department of Health Sciences, University of Genoa, Italy.
Cartiglia
C
C
Lewtas
J
J
De Flora
S
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D012907:Smoking / Q000503:physiopathology
D018736:DNA Adducts; D007527:Isoenzymes; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005982:Glutathione Transferase; D003849:Deoxyguanosine