Role of inflammatory cells in the metabolic activation of polycyclic aromatic hydrocarbons in mouse skin.

Oxidants, such as those generated by activated polymorphonuclear leukocytes (PMNs) during inflammation, have been implicated in the metabolic activation of procarcinogens to their ultimate carcinogenic form. In this study we examined the effect of inflammation on the metabolic activation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) to a covalent binding species in mouse epidermis. Interaction of BP 7,8-dihydrodiol with 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated murine leukocytes resulted in the generation of both a chemiluminescent intermediate and one that covalently bound to the DNA of cocultured epidermal keratinocytes. Topical treatment of mouse skin with TPA led to an influx of PMNs into the skin beginning several hours after application. Myeloperoxidase activity, a marker for neutrophils, increased 15-fold in the skin by 16 hr after TPA treatment. Dual applications of TPA at both 16 hr before and concurrently with administration of [3H]BP 7,8-dihydrodiol led to a 50% enhancement of the level of carcinogen that was covalently bound to epidermal DNA. However, a single application of TPA, either 16 hr before or concurrently with BP 7,8-dihydrodiol administration, had no enhancing effect, suggesting that both initial recruitment of PMNs into the skin and subsequent stimulation of oxidant production by the PMNs were required to enhance carcinogen binding. By contrast, no enhancement of benzo[a]pyrene binding was observed by TPA treatments in vivo. However, TPA-stimulated neutrophils did not activate this procarcinogen to a chemiluminescent metabolite in vitro. These results suggest that oxidants generated by metabolically stimulated PMNs can activate penultimate polycyclic aromatic hydrocarbons, such as BP 7,8-dihydrodiol, to potentially genotoxic metabolites in vivo and further define a role for inflammation in carcinogenesis.