Impact of GSTM1 on aromatic-DNA adducts and P53 accumulation in human skinand lymphocytes

The cellular response to DNA damage is often a p53-mediated cell cycle arre st to provide time for DNA repair or to direct damaged cells into apoptosis . In this study, the impact of glutathione-S-transferase M1 (GSTM1) on DNA damage and subsequent p53-protein accumulation was examined in lymphocytes of healthy volunteers in vitro exposed to benzo[a]-pyrene-diol-epoxide (BPD E) and in skin of atopic eczema patients topically treated with coal tar. D NA adducts were determined by immunocytochemical staining (ICC) and P-32-po stlabelling, P53 accumulation was studied by ICC and the GSTM1 genotype was assessed by polymerase chain reaction. In cultured lymphocytes treated wit h 2.5 muM BPDE for 18 h, increased levels of p53 were found, which were pos itively related to BPDE-DNA adduct levels assessed by ICC (r(s)=0.66, P<0.0 01) and P-32-postlabelling (r(s)=0.56, P<0.001) and appeared to be higher i n GSTM1 (-/-) than in GSTM1 (+) subjects (P=0.003). In skin biopsies of coa l tar treated eczema patients, p53 levels were elevated in 7/10 patients an d a correlation was observed between p53 and DNA adduct levels (r(s)=030, P =0.029). GSTM1(-/-) subjects contained higher levels of p53 in the stratum basale than GSTM1(+) individuals (P=0.026), but no influence of GSTM1 on DN A adduct levels was observed. Thus, P53 accumulates in human skin and lymph ocytes as a protective mechanism against polycyclic aromatic hydrocarbon in duced DNA damage, and this is more pronounced in GSTM1 (-/-) compared to GS TM1(+) individuals. Pharmacogenetics 11:537-543 (C) 2001 Lippincott William s & Wilkins.