Activation of (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to diolepoxides by human polymorphonuclear leukocytes or myeloperoxidase.
Previous studies have demonstrated that the interaction of (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(+-)-B[a]P-7,8-diol] with 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human polymorphonuclear leukocytes (PMNs) elicited genotoxic effects in bacteria and mammalian cells. Structure-activity studies with various polycyclic aromatic hydrocarbon derivatives suggest that a diolepoxide intermediate(s) was being formed from this chemical-cell interaction. In this study, we demonstrate by stereochemical analysis of tetraol products that primarily anti-diolepoxides are being formed from (+-)-B[a]P-7,8-diol by TPA-stimulated PMNs with an anti/syn ratio of 6. Likewise, a myeloperoxidase (MPO)-H2O2 system generated primarily anti-diolepoxides of B[a]P-7,8-diol with an anti/syn ratio greater than 5. Such ratios are indicative of the epoxidation of B[a]P-7,8-diol via a peroxyl radical or a ferryl oxygen transfer-mediated reaction. Addition of azide, an MPO inhibitor, resulted in decreased tetraols from B[a]P-7,8-diol by PMNs or the MPO system. These studies further support the concept that the activation of B[a]P-7,8-diol by PMNs could create a highly localized genotoxic environment which could impact on human health.
Mallet
W G
WG
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
Mosebrook
D R
DR
Trush
M A
MA
D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004101:Dihydroxydihydrobenzopyrenes; C017228:benzo(a)pyrene 7,8-dihydrodiol; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate