Toxicity of processed red meat: Endogenous synthesis of different heme species and their potential implication in colon cancer formation

加工红肉的毒性：不同血红素种类的内源合成及其对结肠癌形成的潜在影响

• 批准号: 495865234
• 负责人: Dr. Tina Kostka
• 金额: --
• 依托单位: Institut für Lebensmittelwissenschaft und Humanernährung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/495865234?language=en
• 关键词: Toxicity; processed; red; meat; Endogenous

Epidemiological studies show a correlation between the consumption of processed meat and the incidence of colorectal cancer. Although the causes and mechanisms have not yet been clearly identified, nitrosylated heme, which is formed when curing salts are added to meat, was long considered to be one of the most important factors. However, this hypothesis has been put to question, for the first time, by the preliminary work of the applicant. In addition, these results brought the substance β-hematin as a possible endogenously formed carcinogen into focus, which was completely unknown in a food (toxicology)-related context until then, although adverse effects of this compound on macrophages and pneumocytes have been described. Moreover, scientific literature shows that β-hematin can be formed in mammalian organs under certain conditions. Therefore, a human exposure, e.g., after consumption of processed meat, would be possible. In the context of the pro-carcinogenic effects of processed meat, β-hematin has not yet been considered. There are no studies on its occurrence as a component of human diet and digestion, nor have the toxic effects on the intestinal epithelium been analyzed. It is therefore the aim of the present project to close these research gaps.It is envisaged to link, for the first time, β-hematin with human nutrition and its endogenous formation as a degradation product of different heme species, which will be demonstrated by using in vitro digestion techniques. The focus is thereby on the detection of structural changes, as well as the formation of new heme-based substances specific to the individual compartments of the human digestive system (oral cavity, stomach, small intestine and colon). Firstly, the interplay of putatively important factors in β-hematin formation (e.g., the presence of a lipid layer, an acidic pH, and nitrosylated heme as a precursor for β-hematin) will be examined individually and in combination. Digestion would be performed using both individual heme species, but also with processed red meat and meat in combination with nitrite-rich vegetables. In the second step, the potentially toxic effects of the endogenously occurring heme species would be analyzed individually and in combination, taking into account physiologically relevant concentrations. Established tumor cell lines of the human colon, either in the form of differentiated epithelial cells or as co-culture with macrophages, will serve as models. The aim is to investigate the compound-specific induction of oxidative stress, DNA damage, an inflammatory response, damage to membrane integrity as well as to investigate the signal transduction pathways underlying these effects. Ultimately, effective preventive measures can be developed as an alternative to a vegetarian diet only when substances actually present in the digestive system, their endogenous activation, their respective distribution within the intestines and their toxic effects are known.

流行病学研究表明，食用加工肉制品与结直肠癌发病率之间存在相关性。虽然原因和机制尚未明确，但长期以来，人们一直认为亚硝基化血红素是最重要的因素之一。亚硝基化血红素是在肉类中加入腌制盐时形成的。然而，申请人的初步工作第一次对这一假设提出了质疑。此外，这些结果使β-血红素物质作为一种可能的内源性致癌物成为人们关注的焦点，尽管该化合物对巨噬细胞和肺细胞的不良影响已被描述，但在此之前，在与食品（毒理学）相关的背景下，人们对其完全未知。此外，科学文献表明，在一定条件下，β-血红素可以在哺乳动物器官中形成。因此，人类有可能在食用加工肉类后接触到这种物质。在加工肉类的致癌作用的背景下，β-血红素尚未被考虑。目前还没有关于其作为人类饮食和消化组成部分的研究，也没有对其对肠上皮的毒性作用进行分析。因此，本项目的目的是缩小这些研究差距。预计将首次将β-血红素与人类营养及其作为不同血红素种类的降解产物的内源性形成联系起来，这将通过使用体外消化技术来证明。因此，重点是检测结构变化，以及针对人类消化系统（口腔、胃、小肠和结肠）的各个腔室（口腔、胃、小肠和结肠）的新血红素基物质的形成。首先，在β-血红素形成过程中假定的重要因素之间的相互作用（例如，脂质层的存在、酸性pH和作为β-血红素前体的亚硝基化血红素）将被单独和联合检查。消化既可以使用单个血红素品种，也可以使用加工过的红肉和肉类与富含亚硝酸盐的蔬菜结合使用。在第二步，内源性血红素物种的潜在毒性作用将单独和组合分析，同时考虑到生理相关浓度。已建立的人结肠肿瘤细胞系，无论是分化的上皮细胞形式，还是与巨噬细胞共培养的形式，都可以作为模型。目的是研究氧化应激、DNA损伤、炎症反应、膜完整性损伤的化合物特异性诱导，以及研究这些影响背后的信号转导途径。最终，只有了解消化系统中实际存在的物质、它们的内源性激活、它们在肠道内的各自分布和它们的毒性作用，才能开发出有效的预防措施，作为素食的替代品。