Several studies have indicated a correlation between the presence of inflammation and the development of cancer. The aim of our study was to determine if pulmonary neutrophils could transform the proximate respiratory carcinogen (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol), to an ultimate carcinogenic metabolite via myeloperoxidase (MPO). To test this hypothesis, virus-free male DBA/2 mice were exposed by inhalation to the Gram-negative bacteria Proteus mirabilis for 1 h. For various time points post-exposure, bronchoalveolar lavage (BAL) was performed to determine total and differential cell counts, cellular MPO activity and production of superoxide. Twelve hours after the exposure, cellular activity of MPO as well as percentage and total number of polymorphonuclear leukocytes peaked and declined thereafter. At this same time point, cells from BAL exhibited increased release of superoxide, as measured by reduction of cytochrome c, after addition of soluble or particulate stimuli, 12-O-tetradecanoylphorbol-13-acetate (TPA) or opsonized zymosan respectively. These cells also elicited biotransformation of B[a]P-7,8-diol as evidenced by enhanced B[a]P-7,8-diol-derived chemiluminescence, tetraol formation and covalently bound adduct formation to exogenous DNA upon addition of TPA or opsonized zymosan. Moreover, the cell-free BAL fluid of infected mice contained substantial MPO activity in comparison to that of uninfected animals. Also, MPO enhanced the binding of B[a]P-7,8-diol to lung DNA in vitro. Unlike previous work emphasizing the potential roles of oxygen free radicals in tumor promotion, our results indicate a role of neutrophilic MPO in the initiation of carcinogenesis.
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.
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