Initiation of nasal and paranasal carcinogenesis by N-nitrosobis(2- oxopropyl)amine (BOP) may be sex hormone-dependent. Although testosterone (T) seems the responsive hormone, a role of estrogen (E) cannot be ruled out. In short-term experiments the patterns of several microsomal enzymes believed to be involved in nitrosamine carcinogenesis, e.g., cytochromes P-450, NADPH- cytochrome P-450 reductase, epoxide hydrolase, and glutathione X- transferase isozymes, will be examined by immunohistochemistry in sexually immature and mature male rats, castrated rats, and in castrated T- or E-treated rats. Also activities of P-450 isozymes, particularly those with sex hormone-dependent functions, will be investigated in nasal mucosa and livers of these rats. Hydroxylation of radiolabeled T, benzphetamine N-demethylation, 7- ethoxy-coumarin O-deethylation, and aniline hydroxylation will be examined to measure enzyme activities. The capability of nasal mucosal homogenate to activate BOP to mutagen(s) will be studied by the Ames and V-79 assays in rats under the above treatment conditions. Quantities of known BOP metabolites generated in vitro will be assessed, and the presence of 06-methylguanine, 7- methylguanine and 04-methylthymine in nasal mucosa of BOP-treated rats will be examined by biochemical and immunohistochemical methods. 1) Is there a correlation between the concentration of sex hormones and the patterns, activities, and capabilities of nasal mucosal enzymes to activate BOP to mutagens? 2) Are there correlations between these enzymes and patterns of alkylated bases and of BOP metabolites? 3) Are there correlations between metabolizing activities, mutagenesis, alkylated bases? 4) Are there qualitative and/or quantitative changes in the patterns and/or activities of nasal mucosal enzymes during nasal- carcinogenesis, and if so, can these changes be early markers for carcinogenesis?
| Kazakoff, K; Iversen, P; Lawson, T et al. (1994) Involvement of cytochrome P450 2E1-like isoform in the activation of N-nitrosobis(2-oxopropyl)amine in the rat nasal mucosa. Eur J Cancer B Oral Oncol 30B:179-85 |
| Lawson, T A (1990) Activation of N-nitrosobis(2-oxopropyl)amine by liver and nasal mucosa tissue from intact and castrated male rats. Cancer Lett 53:39-43 |
| Pour, P M; Kazakoff, K (1989) Prevention of rectal cancer induced by N-nitrosobis(2-oxopropyl)-amine by exogenous testosterone in MRC rats. Carcinogenesis 10:2015-7 |
| Pour, P M; Stepan, K R (1988) The role of testosterone in the nasal cavity tumors induced by N-nitrosobis(2-oxopropyl)amine in rats. Carcinogenesis 9:1417-20 |
