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

基本信息

批准号：
7769738
负责人：
SIDNEY S MIRVISH
金额：
$ 21.57万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769738
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 Genus Cola 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

项目摘要

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）：亚硝酸盐保存（“加工”）肉是据报道结肠癌的原因。这可能会发生，因为加工的肉含有诱导癌症的N-亚硝基化合物（NOC）。以前，PI组表明，在化学系统中，抗坏血酸盐的添加大大降低了NOC的形成。在此基础上，肉类工业现在在加工肉中加入500 mg/kg钠红土（一种抗坏血酸异构体）以及120 mg/kg的硝酸钠（Nano2），以减少NOC形成。我们最近报道，热狗含有5.5 nmol/g的总非挥发性明显NOC（ANC）。通过AMES检测，ANC是诱变的，并在小鼠结肠中引起的异常隐窝（一种前病变）。我们希望了解这些ANC在结肠癌病因学中所扮演的角色，并希望学习如何减少对这些ANC的接触，因此，我们现在提出了5个具体目标。目标1：在这里准备的热狗馅饼的ANC含量不同的影响：我们将测试在这里准备的nano2和na erythorbate对ANC对ANC的效果，当我们在此处准备的热狗馅饼中，当我们从500 mg/kg，下nano2逐步提高了500至7,500 mg/kg，从120和60和0 m/kg/kg/kg/kg/kg升级时，我们将在此处准备。如果我们的观点是正确的，那么我们在此目标中的发现可能会导致肉类行业的变化，从而防止每年成千上万的结肠癌死亡。 AIM 2：识别热狗ANC前体（ANCP）：我们将通过吸附 - 吸附和各种HPLC系统从标准的热狗馅饼中净化ANCP，并尝试通过质谱识别ANCP。我们将合成并表征ANCP N-1-葡萄糖基甘氨酸，其N-亚硝基衍生物以及由其他糖和氨基酸制备的类似物。 AIM 3：诱变测试：我们将使用AMES测试检查在标准条件下制造的硝化ANC的诱变性，并从标准条件下制造的热狗馅饼，从饲喂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的大鼠的粪便中。 AIM 4：渗透研究：为了测试结肠粘膜中的ANC是否可以吸收结肠内腔中的ANC，我们将使用并排扩散室检查纯化的热狗衍生的ANC通过小鼠结肠壁的渗透。 AIM 5：纳米2和Hemin诱导异常隐窝：像热狗一样，饮食纳米2，尤其是与Hemin一起，小鼠的粪便ANC排泄增加，但Nano2不是结肠癌。由于热dog的ANC诱导结肠异常隐窝（结肠癌的前体病变），并且这种诱导可能是由于结肠中的ANC水平升高引起的，因此我们将测试Nano2和Hemin是否也会提高粪便ANC水平，从而诱导小鼠的结肠异常。公共卫生相关性：从加工（亚硝酸盐保留的）肉类得出的项目叙事明显的N-硝基化合物（ANC）可能是与加工肉类（如热狗）相关的结肠癌的原因。我们建议测试用于准备热狗的固化混合物中的改变是否会减少该食物的ANC含量。这种改变可以显着降低结肠癌的发生率。我们还计划从化学识别这些ANC的成分，确定热狗ANC馏分及其组件的诱变，并确定热狗ANC是否可以穿透小鼠结肠壁。我们将测试像热狗ANC一样增加小鼠粪便ANC水平的亚硝酸钠是否表现得像热狗ANC在小鼠结肠中诱导异常隐窝（结肠癌的预科病变）中的表现。