Agaricus bisporus (AB), the cultivated mushroom of commerce, contains several hydrazines and a diazonium ion. We reported earlier that two of these compounds, the N'-acetyl-4-(hydroxymethyl)phenylhydrazine and the 4-(hydroxymethyl)benzenediazonium tetrafluoroborate, induced tumors in five tissues of Swiss mice. We demonstrated the carcinogenicity of the sulfate form of the diazonium ion, thus discounting the possibility that the tetrafluoroborate salt acted as a co-carcinogen. In addition, we have convincingly shown for the first time the presence of two hydrazines p-hydrazinobenzoic acid and beta-N-[gamma-L(+)-glutamyl]-4-carboxyphenylhydrazine in the mushroom. Furthermore, using cytochrome P-450 mixed function oxidases and prostaglandin (H) synthase enzyme, we demonstrated in vitro the metabolism of several mushroom hydrazines, which leads to the possibility that reactive carcinogenic metabolites can be produced intracellularly. Studies are also underway to demonstrate the possible carcinogenicity of two additional mushroom hydrazines, as well as of the mushroom itself, and to reveal the reactions of arenediazonium salts with deoxynucleosides and DNA. In the new proposal we plan to extend our studies to 1) reinvestigate the cancer-inducing ability of 4-(hydroxymenthyl)benzenediazonium sulfate by gavage at MTD and fractions of MTD; 2) determine the possible tumorigenicity in mice of two hydrazine derivatives: beta-N-[gamma-L(+)-glutamyl]-4-formylphenylhydrazine and beta-N-[gamma-L(+)glutamyl]-4-methylphenylhydrazine, the postulated intermediates in agaritine biosynthesis; 3) analyze AB grown by us using radiolabeled compounds for the presence of other hydrazines, the postulated precursors of agaritine; 4) study and compare the metabolism and activation of mushroom hydrazines by cytochrome P-450 and prostaglandin (H) synthase from target and non-target organs; 5) investigate the activity of gamma-glutamyl-transpeptidase under various cooking conditions mimicking the human exposure conditions; 6) synthesize the above and other chemicals for analytical biochemical, toxicity and carcinogenicity investigations. Positive findings from these studies would lead us to the possibility that some human cancer could be caused by these naturally occurring ingredients of the human diet. In addition, the proposed studies on the mechanism of action of the mushroom hydrazines and related chemicals might help to elucidate and to understand the molecular basis of carcinogenesis. The estimated US AB consumption totaled approximately over 280 million kilograms in 1981-82.

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Powell, Jeannine H; Gannett, Peter M (2002) Mechanisms of carcinogenicity of aryl hydrazines, aryl hydrazides, and arenediazonium ions. J Environ Pathol Toxicol Oncol 21:1-31
Gannett, P M; Ye, J; Ding, M et al. (2000) Activation of AP-1 through the MAP kinase pathway: a potential mechanism of the carcinogenic effect of arenediazonium ions. Chem Res Toxicol 13:1020-7
Gannett, P M; Powell, J H; Rao, R et al. (1999) C8-Arylguanine and C8-aryladenine formation in calf thymus DNA from arenediazonium ions. Chem Res Toxicol 12:297-304
Toth, B; Gannett, P; Visek, W J et al. (1998) Carcinogenesis studies with the lyophilized mushroom Agaricus bisporus in mice. In Vivo 12:239-44
Toth, B; Patil, K; Erickson, J et al. (1998) Carcinogenesis by benzenediazonium sulfate in mice. In Vivo 12:379-82
Toth, B; Erickson, J; Gannett, P (1997) Lack of carcinogenesis by the baked mushroom Agaricus bisporus in mice: different feeding regimen [corrected] In Vivo 11:227-31
Gannett, P M; Shi, X; Lawson, T et al. (1997) Aryl radical formation during the metabolism of arylhydrazines by microsomes. Chem Res Toxicol 10:1372-7
Gannett, P M; Lawson, T; Miller, M et al. (1996) 8-Arylguanine adducts from arenediazonium ions and DNA. Chem Biol Interact 101:149-64
Toth, B (1996) A review of the antineoplastic action of certain hydrazines and hydrazine-containing natural products. In Vivo 10:65-96
Toth, B; Gannett, P (1993) Agaricus bisporus: an assessment of its carcinogenic potency. Mycopathologia 124:73-7

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