FALSE MOREL HYDRAZINES: CARCINOGENESIS AND CHEMISTRY

美国每年约有10万人食用 羊肚菌Gyromitra esculenta 这种真菌含有11种 肼类似物，其中乙醛甲酰基腙（AMFH）， N-甲基-N-甲酰肼（MFH）和N-甲基肼（MH）被证明是 在这个实验室的老鼠身上是致癌的。 在本建议中，我们打算（1） 通过体外诱癌试验， 小鼠终身喂养研究，（2）研究 3-甲基丁醛、N-甲基-N-甲酰腙和己醛 N-甲基-N-甲酰腙成分的蘑菇通过终身口服 给药小鼠，（3）通过每周重复胃内给药研究 MFH和MH的致癌性， （4）化学测定小鼠体内AMFH、MFH和MH的含量， 食用菌用于饲养试验，（5）研究 在丙二醇中灌胃给药后的AMFH、MFH和MH， 水使用全身放射自显影，（6）调查 MFH、MH和甲酰肼（FH）的电化学氧化， 自由基捕获剂，（7）在体外和体内研究 使用细胞色素P450、黄素单加氧酶和 前列腺素（H）合酶系统，和（8）以确定程度和 DNA烷基化的性质，特别强调的形成和 使用敏感的06-甲基鸟嘌呤和04-甲基胸腺嘧啶的持久性 单克隆抗体/放射免疫分析技术。 的结果 拟议的研究将使我们能够确定环境的重要性， 蘑菇消费及其毒素，并揭示其作用机制， 三种主要的致癌肼，特别是MFH（迄今为止最 这一系列的致癌物质）。 最近的一项研究喂养另一个新鲜的 蘑菇，栽培的双孢蘑菇，诱导了多种肿瘤， 动物 拟议的实验可能会在以下方面提供积极的发现： 当前高度关注的领域。 事实上，我们对 这些高致癌性肼的作用机制。 我们提出的 研究应确定氧化过程，并应阐明 酶系统参与。

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.