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?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA035042-04A2
Application #
3172800
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1984-04-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Overall Medical
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198