CAPSAICIN: CHEMISTRY, CARCINOGENESIS, AND MODE OF ACTIO

美国和世界人口消费了大量的辣椒。 辣椒素，辣椒的辛辣原理，在大量的 在辣椒属的物种中(高达0.53%)。在预赛中 实验证明，辣椒素具有诱变活性。 在Ames化验中。我们还表明，口服给药 辣椒素可诱发小鼠肠道肿瘤。在本提案中 我们计划：(1)测定辣椒素的诱变活性，它的 小鼠伤寒沙门氏菌试验中辣椒的纯同系物和提取物； (2)评价辣椒素及其同系物和辣椒素的诱变能力 (2)评价辣椒素的诱变能力，其 金黄地鼠肝细胞-V79中辣椒的同源成分和提取物 哺乳动物试验；(3)半合成饲料饲喂试验 辣椒素对小鼠的致瘤性；(4)通过灌胃确定 灌胃辣椒素对小鼠的致瘤作用；(5)研究 用半合成饲料喂养小鼠，观察热致瘤性 红(干)辣椒；(6)比较放射性标记辣椒素的代谢。 小鼠十二指肠(靶组织)、肝脏(可能)的亚细胞组分 靶组织)和肺和结肠(非靶组织)。我们将使用 细胞色素P-450依赖的单加氧酶和前列腺素(H)合酶 系统。任何形成的反应性代谢物都会被捕获 谷胱甘肽(GSH)和谷胱甘肽-代谢物复合体的性质 下定决心。我们还将：(7)评估放射性标记辣椒素的水平 及其在血液、粪便和尿液中的代谢；(8)研究 H3-辣椒素及其同系物和金属代谢物在体外相互作用 和(9)合成放射性标记的辣椒素和 二氢辣椒素。我们将分离出足够纯量的 辣椒素及其同系物的高效液相色谱分析用于其他研究。这些 研究旨在确定辣椒的生物效应和 辣椒素在体外和在INVO实验中。关于调查的 辣椒素的作用机制有望阐明该酶 负责新陈代谢的系统和组织。DNA结合研究 将表明两个潜在的结合位点的重要性 辣椒素分子。毫无疑问，自然产生的化学致癌物 在饮食中发现的可能是致病的主要因素 重要的人类癌症。因此，热辣椒的消费量 美国和世界人口可能会造成有害影响。

The U.S. and the world population consume large amounts of hot peppers. Capsaicin, the pungent principle of hot pepper, was found in substantial mounts (up to 0.53%) in the species of the genus Capsicum. In preliminary experiments, we demonstrated that capsaicin exhibited mutagenic activitty in the Ames assay. We have also shown that the oral administration of capsaicin induced a few intestinal tumors in mice. In the present proposal we plan to: (1) determine the mutagenic activity of capsaicin, both its pure homologues and extracts of hot red pepper in the S. typhimurium assay; (2) assess the mutagenic ability of capsaicin, both its homologues and murium assay; (2) assess the mutagenic ability of capsaicin, both its homolgues and extracts of hot pepper in the hamster hepatocyte-V79 mammalian test; (3) study, by feeding experiment using semisynthetic diet in mice, the tumorigenicity of capsaicin; (4) determine by intragastric gavages the tumorigenic action of capsaicin in mice; (5) investigate in a feeding study, using semisynthetic diet in mice, the tumorigenicity of hot red (dried) pepper; (6) compare the metabolism of radiolabeled capsaicin by subcellular fractions from mouse duodenum (target tissue), liver (possible target tissue) and from lungs and colon (non-target tissues). We will use the cytochrome P-450-dependent monooxygenase and prostaglandin (H) synthase systems. Any reactive metabolites that are formed will be trapped with glutathione (GSH) and the nature of the GSH-metabolite complex will be determined. We will also: (7) assess the levels of radiolabeled capsaicin and its metabolitesin the blood, feces and urine; (8) study the ability of H3-capsaicin, its homologues and metal metabolites to interact in vitro and in vivo with DNA; and (9) synthesize radiolabeled capsaicin and dihydrocapsaicin. We will will isolate sufficient pure quantities of capsaicin and its homologues by HPLC for other investigations. These studies are designed to determine the biological effects of hot pepper and capsaicin in vitro and in invo experiments. Investigations on the mechanisms of action of capsaicin will hopefully elucidate the enzyme systems and tissues responsble for metabolism. The DNA binding studies will indicate the importance of the two potential binding sites of capsaicin molecule. Undoubtedly, naturally occurring chemical carcinogens found in the diet are probably the major factors in the etiology of important human cancers. Consequently, the consumption of hot Capsicums by the U.S. and world population may result in harmful effects.