Polynuclear aromatic hydrocarbons (PAH) are important environmental carcinogens, which are particularly abundant in automobile exhaust, cigarette smoke, and polluted city air. Carcinogenic PAH require activation in order to react with biological macromalicules to express their tumorigenic activity. In the present proposal by a systematic study of: (1) The time course of formation of metabolites of [3H]benzo(a)pyrene (BaP) or its derivatives in mouse epidermis in vivo; (2) The time course of formation of DNA adducts from reaction of [3H]BaP metabolites in mouse epidermis; and (3) The rates of disappearance of [3H]BaP or its derivatives from mouse epidermis, we propose to determine: (a) The mechanistic basis by which the environmental cocarcinogen catechol, an abundant phenolic compound in cigarette smoke, enhances the tumorigenicity of BaP on mouse skin. Preminary data suggest that catechol inhibits conjugation pathways of BaP metabolism. (b) The mechanistic basis by which 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) the presumed ultimate metabolic carcinogen of BaP is less tumorigenic than the parent hydrocarbon BaP on mouse skin. The results of these studies will provide valuable information on the mechanism(s) of carcinogenicity of catechol and the role of BPDE as an ultimate carcinogen of BaP in mouse skin. The above methodology also will be useful in testing the bay region theory or exploring the mechanism(s) of other PAH cocarcinogens or inhibitors.
| Melikian, A A; Hecht, S S; Hoffmann, D (1989) Mechanistic studies of tobacco carcinogenesis in mouse epidermis and lung tissues. Prog Clin Biol Res 298:331-45 |
| Melikian, A A; Bagheri, K; Hecht, S S (1987) Contrasting disposition and metabolism of topically applied benzo(a)pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mouse epidermis in vivo. Cancer Res 47:5354-60 |
| Melikian, A A; Leszczynska, J M; Hecht, S S et al. (1986) Effects of the co-carcinogen catechol on benzo[a]pyrene metabolism and DNA adduct formation in mouse skin. Carcinogenesis 7:9-15 |
