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 an d their excretion as water-soluble conjugates, Conjugation of GSH with elec trophiles is catalyzed by GSH S-transferases (GST), which constitute a broa d family of phase II isoenzymes, Two of the GST encoding genes, GSTM1 (mu) and GSTT1 (0), have a null genotype due to their homozygous deletion that r esults 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 demo nstrated that DNA adducts are consistently detectable in smooth muscle cell s (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 ge notype, 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 ep idemiology 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.