INFLUE HETEROCYCLIC AMINE METABOLIC POLYMORPH ON BIOACTIVAT PHIP IN HUMAN COLON

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究的主要目的是通过证明NAT 2和CYPIA 2表型以及GSTM 1和CYPIA 1基因型与给予饮食相关水平14 C-PhIP的人体中形成的PhIP-DNA加合物水平相关，确认PhIP代谢在结肠癌中的作用。这些因素对于研究很重要，因为它们代表了基于啮齿动物研究被认为在PhIP代谢中很重要的酶。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具有活性。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。 我们收集了人体数据，通过确定NAT 2和CYPIA 2表型之间的关系，以及GSTM 1和CYPIA 1基因型和人体中形成的PhIP-DNA加合物水平，确定PhIP代谢在结肠癌中的作用。这是通过给予非常低水平的14 C-标记的PhIP与结肠癌的诊断谁是预定手术的人类受试者来实现的。迄今为止，来自10名受试者的数据表明，SULT、NAT 2和CYP 1A 2表型影响结肠中的加合物水平。计划进行一项更大规模、更具统计学意义的研究，以验证这些发现。 有必要在其他癌症如乳腺癌、前列腺癌和肺癌中进行类似的工作。在这些地区中，疾病造成的死亡人数都很高，预防战略受到疾病病因学和代谢途径方面知识不足的限制，而且接触信息不完整。

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.