Myeloperoxidase-enhanced formation of (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a] pyrene adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen

Abstract

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.

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…Each diastereomer may in turn exist as a pair of enantiomers, or mirror images of each other [(+)-and (-)-syn-DE in Figure 8, respectively]. This step may be carried out by CYP1A1, peroxidase-catalyzed epoxidation, or through cooxidation by simultaneous exposure to B[a]P and sulfur or nitrogen oxides (Cavalieri and Rogan 1995;Constantin et al 1994;Petruska et al 1992;Thakker et al 1985). In addition to CYP1A1, cytochrome P450 isoenzymes such as CYP1A2, CYP1B1, and CYP3A4 may also participate in the metabolic activation of PAHs (Guengerich 1993;Kim et al 1998;Nelson et al 1996).…”

NQO1, MPO, and the risk of lung cancer: A HuGE review

“…8,9 MPO has been shown to activate an intermediate metabolite of BP, the 7,8-diol BP, to the highly reactive and carcinogenic benzo(a)pyrene 7,8-diol-9,10 epoxide (BPDE) 10 and to enhance the binding to BPDE to lung DNA in vitro. 11 MPO also activates carcinogens in tobacco smoke including polycyclic aromatic hydrocarbons (PAHs), 10 -12 aromatic amines, [13][14][15] and heterocyclic amines 16 and catalyzed the endogenous formation of carcinogenic free radicals. 17 MPO may also function as an antimicrobial agent in neutrophils by catalyzing the production of genotoxic hypochlorous acid and other reactive oxygen species.…”

Genetic susceptibility to tobacco-related cancer

“…A significant proportion (25-40%) of the hydrogen peroxide formed by activated neutrophils may be converted to hypochlorous acids. MPO metabolically activates a wide range of tobacco smoke mutagens and environmental pollutants to DNAdamaging metabolites, including aromatic amines, the promutagenic derivatives of PAHs and heterocyclic amines (Petruska et al, 1992;Williams et al, 1998). The MPO gene is located on chromosome 17.…”