A single dose of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) or 2-ethynylnapthalene (EN) was applied to the skin of SENCAR mice 5 min before an initiating dose of 7,12dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (B[a]P) and the development of skin tumors then promoted with biweekly topical applications of 12-O-tetradecanoylphorbol-13-acetate (TPA). The application of EP strongly inhibited the formation of skin tumors initiated by either DMBA or B[a]P in a dose-dependent manner. Application of 44 pmol of EP inhibited tumor initiation by 10 nmol of DMBA approximately 25%; application of 440 nmol of EP inhibited tumor initiation by 200 nmol of B[a]P approximately 51%. A high single dose of EP (4.4-44-mu-mol) nearly eliminated skin tumor initiation by either 10 nmol of DMBA or 200 nmol of B[a]P. Application of VP also inhibited the formation of skin tumors initiated by either DMBA or B[a]P in a dose-dependent manner, but higher doses of VP than of EP were required to produce comparable inhibitions. Application of 44 nmol of VP inhibited tumor initiation by 10 nmol of DMBA approximately 30%; application of 4.4-mu-mol of VP inhibited tumor initiation by 200 nmol of B[a]P approximately 56%. Application of EN yielded contrasting results. EN inhibited the formation of skin tumors initiated by 10 nmol of DMBA, but the observed dose-dependence was minimal; tumors were decreased about 40% by 3.3-mu-mol of EN and only about 65% by 132-mu-mol of EN. A high single dose of EN (132-mu-mol) increased both the mean number of tumors per mouse and the percentage of mice that developed tumors after initiation by 200 nmol of B[a]P. Topical application of 4.4-mu-mol of EP, 22-mu-mol of VP or 33-mu-mol of EN to the skin of SENCAR mice 5 min before a single initiation dose of 2.5-mu-mol of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) had a minimal inhibitory effect (14-28%) on the development of skin tumors produced by subsequent biweekly promotion with TPA. A single dose of 44-mu-mol of EP or 132-mu-mol of EN followed by biweekly applications of TPA did not produce skin tumors; however, a dose of 44-mu-mol of VP followed by promotion with TPA produced a low but significant number of skin tumors. Except for the inhibition of B[a]P-initiated skin tumorigenesis by VP, the observed inhibitions of polycyclic aromatic hydrocarbon (PAH) tumorigenesis by EP, VP and EN corresponded with the inhibitions of PAH-DNA adduct formation in mouse skin by these agents previously reported. VP was more effective at preventing B[a]P-initiated tumorigenesis than anticipated based upon its inhibition of B[a]P-DNA adduct formation in mouse epidermis. These data are discussed in terms of the potential of the pyrene moiety of EP and VP to direct binding preferentially to the active sites of P450 isozymes involved in PAH activation and of the ethynyl group of EP to function additionally as a mechanism-based inactivator (suicide inhibitor) of certain of these P450 isozymes.
