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.