We will study the metabolism and action of methyl-n-amylnitrosamine (MNAN) in the esophagus as follows: (1) We will examine the production of hydroxy and keto metabolites of MNAN in freshly removed esophagus, forestomach and other tissues of rodents. We will complete studies of changes with age of this metabolism in key tissues of suckling rats and hamsters, determine whether these changes are due to intrinsic or extrinsic factors, examine effects of agents that induce individual P-450s, and determine configurations of the hydroxy-MNAN metabolites. (2) We will develop systems for culturing adult rat esophagus, while still maintaining MNAN metabolism. We will study MNAN metabolism in cultures of newborn and adult rat forestomach, hamster forestomach and hamster esophagus, and by freshly incubated adult and fetal human esophagus, and study effects of inducers and other agents on these cultures. (3) We will examine MNAN metabolism by rat liver and esophageal microsomes and reconstituted cytochrome P-450 (""""""""P-450"""""""") systems to determine which P-450s metabolize MNAN. Gel electrophoresis and specific antibodies will identify the individual P-450s in adult and developed esophagus and forestomach. (4) We will examine MNAN alkylation of DNA to give 06- and N7 alkylguanine and 04-alkylthymine, using 3H-MNAN or radioimmunoassay. In vivo persistence of alkylated bases in esophageal DNA will be measured, and DNA alkylation by 2- and 4-oxo-MNAN. (5) We will determine whether MNAN is taken up more extensively than dimethylnitrosamine by rat esophagus. (6) We will compare carcinogenicity of MNAN injected into newborn, 3-day-old and adult rats and hamsters, test for carcinogenicity of 2- and 4-oxo-MNAN in adult rats, and determine whether inducers can affect MNAN carcinogenicity. These studies are designed to investigate (a) why MNAN is a specific carcinogen for the rat esophagus, (b) what intrinsic or extrinsic factors control the striking changes in MNAN metabolism from newborn to adult rats and hamsters, and (c) whether human esophagus could be susceptible to nitrosamine carcinogenesis.

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National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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University of Nebraska Medical Center
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Zhou, Lin; Mirvish, Sidney S (2005) Inhibition by allyl sulfides and crushed garlic of O6-methylguanine formation in liver DNA of dimethylnitrosamine-treated rats. Nutr Cancer 51:68-77
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