Myeloperoxidase - 463A variant reduces benzo[a]pyrene diol epoxide DNA adducts in skin of coal tar treated patients

The skin of atopic dermatitis patients provides an excellent model to study the role of inflammation in benzo[a]pyrene (BaP) activation, since these i ndividuals are often topically treated with ointments containing high conce ntrations of BaP, In this study we have determined, by HPLC with fluorescen ce detection, the BaP diol epoxide (BPDE)-DNA adduct levels in human skin a fter topical treatment with coal tar and their modulation by the -453G -->A myeloperoxidase (MPO) polymorphism, which reduces MPO mRNA expression. BPD E-DNA adduct levels were 2.2 and 14.2 adducts/10(8) nt for MPO-463AA/AG and -463GG, respectively, The predominant BaP tetrol observed was tetrol I-1, which is derived after hydrolysis of the anti-BPDE-DNA adduct, The tetrol I -1/II-2 ratio, corresponding to the anti/syn ratio, was 6,7, The P-32-post- labeling assay was also performed and thin layer chromatograms showed a maj or spot with a chromatographic location corresponding to BPDE-DNA, The mean values of the BPDE-DNA adduct spots were 3.8 +/- 2.4 per 10(8) nt for MPO- 463AA/ AG (n = 3) and 18.4 +/- 11.0 per 10(8) nt for MPO-463GG (n = 7), res pectively (P = 0.03), One individual with the homozygous mutant genotype (- 463AA) even had a 13-fold lower adduct level (1.4 per 10(8) nt) as compared to MPO-463GG subjects. In conclusion, these data show for the first time: (i) the in vivo formation of BPDE-DNA adducts in human skin treated with co al tar; (ii) that the MPO-463AA/AG genotype reduced BPDE-DNA adduct levels in human skin.