Approximately 100,000 people in the U.S.A. annually consume the edible false morel mushroom Gyromitra esculenta. This fungus contains eleven hydrazine analogues, of which acetaldehyde methylformylhydrazone (AMFH), N-methyl-N-formylhydrazine (MFH) and N-methylhydrazine (MH) were shown to be carcinogenic in mice in this laboratory. In this proposal we intend (1) to determine the tumor-inducing ability of the fresh Gyromitra esculenta by a lifelong feeding study in mice, (2) to study the tumorigenicity of 3-methylbutanal N-methyl-N-formylhydrazone and hexanal N-methyl-N-formylhydrazone ingredients of the mushromm by lifelong oral administration to mice, (3) to investigate by repeated weekly intragastric instillations in propylene glycol the carcinogenicity of MFH and MH in mice, (4) to measure chemically the amounts of AMFH, MFH and MH in the mushroom used for the feeding experiment, (5) to study the distribution of AMFH, MFH and MH following administration by gavage in propylene glycol and water using whole-body autoradiography, (6) to investigate the electrochemical oxidation of MFH, MH, and formylhydrazine (FH) with the use of radical trapping agents, (7) to investigate the in vitro and in vivo metabolism of MFH using cytochrome P450, flavin monooxygenase and prostaglandin(H)synthase systems, and (8) to determine the extent and nature of DNA alkylation, with particular emphasis on the formation and persistence of 06-methylguanine and 04-methylthymine using the sensitive monoclonal antibody/radioimmunoassay technique. The results of the proposed study will allow us to determine the environmental significance of mushroom consumption and their toxins and reveal the mechanism of action of the three main carcinogenic hydrazines, particularly MFH (to date the most potent carcinogen of this series). A recent study feeding another fresh mushroom, the cultivated Agaricus bisporus, induced a variety of tumors in animals. The proposed experiments will likely provide positive findings in a field of current high interest. Virtually nothing is known about the mechanism of action of these highly carcinogenic hydrazines. Our proposed studies should identify the oxidative processes and should elucidate the enzyme systems involved.
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