NOC in processed meat as a likely cause of colon cancer

加工肉类中的 NOC 可能是结肠癌的原因

• 批准号: 8196769
• 负责人: SIDNEY S MIRVISH
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2013-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196769
• 关键词: A/J Mouse; Acetonitriles; Adsorption; Age; Amino Acids; Area; Cancer Etiology; Canis familiaris; Carbohydrates; Carcinogens; Cation Exchange Resins; Cessation of life; Characteristics; Chemicals; Clostridium botulinum; Colon; Colon Carcinoma; Color; Consumption; Diet; Diffusion; Dipeptides; Dose; Eagles; Ensure; Esophageal; Etiology; Excretory function; Exposure to; Feces; Flavoring; Food; Fructose; Funding; Gastrointestinal tract structure; Glucose; Glycine; Grant; Hemin; High Pressure Liquid Chromatography; Human; Incidence; Industry; Infusion Pumps; Isomerism; Laboratories; Learning; Lesion; Link; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Meat; Meat Products; Methods; Monitor; Mucous Membrane; Mus; Mutagenesis; Mutagenicity Tests; Mutation; N-terminal; Nitrites; Nitrosamines; Nitrosation; Nitroso Compounds; Paper; Play; Premalignant; Preparation; Procedures; Process; Proteins; Publishing; Rattus; Reaction; Recipe; Reporting; Research; Risk; Role; Salmonella typhimurium; Sampling; Scientist; Side; Skin; Sodium; Sodium Nitrite; Solvents; Surveys; System; Testing; Water; Work; absorption; analog; aqueous; ascorbate; base; beef; carcinogenesis; colon carcinogenesis; drinking water; experience; feeding; improved; male; prevent; public health relevance; reconstitution; research study; silochrome; sugar

DESCRIPTION (provided by applicant): Nitrite-preserved ("processed") meat is a reported cause of colon cancer. This may occur because processed meat contains N-nitroso compounds (NOC), which induce the cancer. Previously, the PI's group demonstrated that addition of ascorbate greatly reduced NOC formation in a chemical system. On this basis, the meat industry now adds 500 mg/kg of sodium erythorbate (an ascorbate isomer) together with 120 mg/kg of sodium nitrite (NaNO2) in processed meat to reduce NOC formation. We recently reported that hot dogs contain 5.5 nmol/g of total non-volatile apparent NOC (ANC). The ANC are mutagenic by the Ames test and induced aberrant crypts (a premalignant lesion) in the mouse colon. We wish to understand the role played by these ANC in colon cancer etiology and wish to learn how to reduce exposure to these ANC, Therefore, we now propose 5 Specific Aims. Aim 1: Effect of varying erythorbate and nitrite levels on ANC content of hot dog patties prepared here: We will test effects of added NaNO2 and Na erythorbate on ANC in hot-dog patties prepared here when we raise erythorbate stepwise from 500 to 7,500 mg/kg, lower NaNO2 from 120 to 60 and 0 mg/kg, or omit both additives. If our views are correct, our findings in this Aim could produce changes in the meat industry that would prevent thousands of deaths each year from colon cancer. Aim 2: Identification of hot dog ANC precursor (ANCP): We will purify ANCP from standard hot dog paties by adsorption-desorption and various HPLC systems, and try to identify the ANCP by mass spectrometry. We will synthesize and characterize the ANCP, N-1-glucosyl glycine, its N-nitroso derivative and analogs prepared from other sugars and amino acids. Aim 3: Mutagenesis tests: We will use the Ames test to examine the mutagenicity of nitrosated ANC prepared from hot dog patties manufactured under standard conditions and those giving minimum ANC levels, from feces of rats fed NaNO2 or hot dogs, and from the reaction of glucose with glycine and other amino acids. Aim 4: Permeation studies: To test whether ANC in the colonic lumen can be absorbed by the colonic mucosa, we will examine permeation of purified hot-dog-derived ANC through the mouse colon wall using side-by-side diffusion chambers. Aim 5: Induction of aberrant crypts by NaNO2 and hemin: Like hot dogs, dietary NaNO2, especially together with hemin, increased fecal ANC excretion in mice, but NaNO2 is not a colon carcinogen. Because hot-dog-derived ANC induced colonic aberrant crypts (a precursor lesion for colon cancer) and this induction was probably caused by the raised ANC levels in the colon, we will test whether NaNO2 and hemin, which also increased fecal ANC levels, induce colonic aberrant crypts in mice. PUBLIC HEALTH RELEVANCE: Project narrative Apparent N-nitroso compounds (ANC) derived from processed (nitrite-preserved) meat are a likely cause of colon cancer associated with processed meat such as hot dogs. We propose to test whether alterations in the curing mixture used to prepare hot dogs will reduce the ANC content of this food. This alteration could significantly reduce the incidence of colon cancer. We also plan to chemically identify components of these ANC, determine mutagenicity of the hot dog ANC fraction and its components, and establish whether hot dog ANC can penetrate the mouse colon wall. We will test whether sodium nitrite which, like hot dog ANC, increased fecal ANC levels in mice, behaves like hot dog ANC in inducing aberrant crypts (a precancer lesion for colon cancer) in the mouse colon.

描述(由申请人提供)： 据报道，亚硝酸盐腌制(“加工”)肉类是导致结肠癌的原因之一。这可能是因为加工肉类含有N-亚硝基化合物(NOC)，而NOC会导致癌症。此前，PI的研究小组证明，添加抗坏血酸大大减少了化学体系中NOC的生成。在此基础上，肉类行业现在在加工肉类中添加500毫克/公斤的异抗坏血酸钠(一种抗坏血酸异构体)和120毫克/公斤的亚硝酸钠(NaNO2)，以减少NOC的形成。我们最近报道，热狗含有5.5nmol/g的总非挥发性表观NOC(ANC)。Ames试验和诱发小鼠结肠中的异常隐窝(癌前病变)使ANC发生突变。我们希望了解这些ANC在结肠癌病因中所起的作用，并希望了解如何减少对这些ANC的暴露，因此，我们现在提出5个具体目标。目的1：不同浓度的赤霉酸和亚硝酸盐对自制热狗肉饼中ANC含量的影响：将赤霉酸从500 mg/kg逐步提高到7500 mg/kg，将NaNO2从120 mg/kg降到60 mg/kg和0 mg/kg，或不添加这两种添加剂，分别测试添加NaNO2和Na_2O_3对制作的热狗肉饼中ANC的影响。如果我们的观点是正确的，我们在这一目标上的发现可能会给肉类行业带来变化，从而防止每年数千人死于结肠癌。目的2：热狗ANC前体(ANCP)的鉴定：采用吸附-解吸和多种高效液相色谱系统从标准热狗样品中分离纯化ANCP，并尝试用质谱法对ANCP进行鉴定。我们将合成和表征ANCP，N-1-葡萄糖基甘氨酸，它的N-亚硝基衍生物以及由其他糖和氨基酸制备的类似物。目的3：致突变试验：我们将使用Ames试验来检测从标准条件下生产的热狗肉饼和ANC含量最低的热狗肉饼中制备的亚硝化ANC的致突变性，来自喂食NaNO2或热狗的大鼠的粪便，以及葡萄糖与甘氨酸和其他氨基酸的反应。目的4：渗透研究：为了检测肠腔内的ANC是否能被结肠粘膜吸收，我们将利用并排扩散箱检测纯化的热狗来源的ANC通过小鼠结肠壁的渗透。目的5：NaNO2和氯化血红素诱导小鼠畸形隐窝：与热狗一样，饮食中的NaNO2，特别是与氯化血红素一起，可增加小鼠粪便ANC的排泄，但NaNO2不是结肠癌的致癌物。由于热狗来源的ANC诱导了结肠畸形隐窝(结肠癌的前驱病变)，而这种诱导可能是由结肠中ANC水平升高引起的，我们将测试NaNO2和氯化血红素是否会诱导小鼠结肠异常隐窝，它们也增加了粪便ANC水平。 公共卫生相关性： 项目简介从加工(亚硝酸盐保存)的肉类中提取的表观N-亚硝基化合物(ANC)可能是与热狗等加工肉类相关的结肠癌的原因。我们建议测试用来制作热狗的腌制混合物的变化是否会降低这种食物的ANC含量。这一改变可以显著降低结肠癌的发病率。我们还计划对这些ANC的成分进行化学鉴定，确定热狗ANC组分及其成分的致突变性，并确定热狗ANC是否可以穿透小鼠结肠壁。我们将测试亚硝酸钠是否像热狗ANC一样增加小鼠粪便ANC水平，在诱导小鼠结肠内异常隐窝(结肠癌的癌前病变)方面是否像热狗ANC一样。

项目成果

Calcium inhibits promotion by hot dog of 1,2-dimethylhydrazine-induced mucin-depleted foci in rat colon.

• DOI: 10.1002/ijc.28286
• 发表时间: 2013-12-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Santarelli, Raphaelle L.;Naud, Nathalie;Tache, Sylviane;Gueraud, Francoise;Vendeuvre, Jean-Luc;Zhou, Lin;Anwar, Muhammad M.;Mirvish, Sidney S.;Corpet, Denis E.;Pierre, Fabrice H. F.
• 通讯作者: Pierre, Fabrice H. F.