Impact of GSTM1 on aromatic-DNA adducts and p53 accumulation in human skin and lymphocytes.
The cellular response to DNA damage is often a p53-mediated cell cycle arrest 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 (BPDE) and in skin of atopic eczema patients topically treated with coal tar. DNA adducts were determined by immunocytochemical staining (ICC) and 32P-postlabelling, p53 accumulation was studied by ICC and the GSTM1 genotype was assessed by polymerase chain reaction. In cultured lymphocytes treated with 2.5 microM BPDE for 18 h, increased levels of p53 were found, which were positively related to BPDE-DNA adduct levels assessed by ICC (rs = 0.66, P < 0.001) and 32P-postlabelling (rs = 0.56, P < 0.001) and appeared to be higher in GSTM1(-/-) than in GSTM1(+) subjects (P = 0.003). In skin biopsies of coal tar treated eczema patients, p53 levels were elevated in 7/10 patients and a correlation was observed between p53 and DNA adduct levels (rs = 0.50, 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 DNA adduct levels was observed. Thus, p53 accumulates in human skin and lymphocytes as a protective mechanism against polycyclic aromatic hydrocarbon induced DNA damage, and this is more pronounced in GSTM1(-/-) compared to GSTM1(+) individuals.
Godschalk
R W
RW
Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands.
Ostertag
J U
JU
Zandsteeg
A M
AM
Van Agen
B
B
Neuman
H A
HA
Van Straaten
H
H
Van Schooten
F J
FJ
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D000328:Adult; D001564:Benzo(a)pyrene / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D003876:Dermatitis, Atopic; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D012867:Skin / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D001564:Benzo(a)pyrene; D018736:DNA Adducts; D005982:Glutathione Transferase; D016159:Tumor Suppressor Protein p53