INFLUE HETEROCYCLIC AMINE METABOLIC POLYMORPH ON BIOACTIVAT PHIP IN HUMAN COLON

影响人结肠中生物活性剂 PHIP 的杂环胺代谢多晶型

• 批准号: 7358995
• 负责人: NICHOLAS PAUL LANG
• 金额: $ 1.76万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358995
• 关键词: INFLUE; HETEROCYCLIC; AMINE; METABOLIC; POLYMORPH

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main objective of this research is to confirm the role of PhIP metabolism in colon cancer by demonstrating that the NAT2 and CYPIA2 phenotype, as well as GSTM1 and CYPIA1 genotype are related to the level of PhIP-DNA adducts formed in humans administered dietary relevant levels of 14C-PhIP. These factors are important to study because they represent enzymes that are thought to be important in PhIP metabolism based on rodent studies. The outcome of this work will be additional proof that heterocyclic amines such as PhIP are involved in colon cancer since these enzymes are active in the metabolism of heterocyclic amines. Additionally, this work will show whether genotype or phenotype are potentially useful markers of PhIP susceptibility for colon cancer. We have collected data in humans to establish the role of PhIP metabolism in colon cancer by determining the relationship between NAT2 and CYPIA2 phenotype, as well as GSTM1 and CYPIA1 genotype and the level of PhIP-DNA adducts formed in humans. This was accomplished by administering very low levels of 14C-labeled PhIP to human subjects with a diagnosis of colon cancer who are scheduled for surgery. Data so far from 10 subjects indicates that SULT, NAT2 and CYP1A2 phenotypes influence adduct levels in the colon. A larger, more statistically significant, study is planned to verify the findings. There is a need to perform similar work in other cancers such as breast cancer, prostate cancer and lung cancer. In each of these areas, the disease toll is great, the prevention strategies are limited by a knowledge deficit in the areas of disease etiology and metabolism pathway and exposure information is incomplete.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的主要目的是通过证明NAT2和CYPIA2表型以及GSTM1和CYPIA1基因型与膳食中相应水平的14C-PhIP形成的PhIP- dna加合物水平相关，从而证实PhIP代谢在结肠癌中的作用。研究这些因素很重要，因为根据啮齿动物的研究，它们代表了在PhIP代谢中被认为很重要的酶。这项工作的结果将进一步证明，杂环胺如PhIP参与结肠癌，因为这些酶在杂环胺的代谢中是活跃的。此外，这项工作将显示基因型或表型是否是结肠癌PhIP易感性的潜在有用标记。我们收集了人类数据，通过确定NAT2和CYPIA2表型，以及GSTM1和CYPIA1基因型与人类形成的PhIP- dna加合物水平的关系，来确定PhIP代谢在结肠癌中的作用。这是通过向诊断为结肠癌并计划进行手术的人类受试者提供极低水平的14c标记PhIP来实现的。到目前为止，来自10名受试者的数据表明，SULT、NAT2和CYP1A2表型影响结肠中加合物的水平。计划进行一项规模更大、统计意义更大的研究来验证这些发现。有必要对乳腺癌、前列腺癌和肺癌等其他癌症进行类似的研究。在这些领域中，疾病造成的损失都很大，预防策略受到疾病病因和代谢途径方面知识不足和暴露信息不完整的限制。