GENOTOXICITY OF ENVIRONMENTAL CHEMICALS IN THE PANCREAS

环境化学物质对胰腺的基因毒性

• 批准号: 6444616
• 负责人: TERENCE A LAWSON
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-25 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444616
• 关键词: DNA damage; DNA repair; acyltransferase; chemical carcinogen; chemical carcinogenesis; cyclic amine; cytochrome P450; disease /disorder proneness /risk; environmental toxicology; enzyme activity; gene mutation; glutathione transferase; hamsters; human tissue; laboratory rat; nitrosamines; pancreas neoplasms; toxin metabolism

There is compelling evidence for a role for two types of chemical, tobacco specific nitrosamines and heterocyclic amines, in the induction of pancreatic ductal adenocarcinoma in humans. There are animal models for this form of cancer involving tobacco specific nitrosamines and other experimental evidence implicating heterocyclic amines. We propose to examine the actions of a representative amine (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine (PhlP) and nitrosamine (4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)) and the carcinogenic nitrosamine MIP (N-nitrosomethyl (2-oxopropyl)amine) in pancreatic duct epithelial cells (DEC) from humans and from the appropriate rodent species and strains. We will concentrate on the metabolic activation of these chemicals focussing on the enzyme(s) that are involved in their metabolism. Our aim here is to determine those enzymes that may predispose humans to the pancreatrophic actions of environmental chemicals and to attempt to define groups who are at risk for pancreas cancer induction. We will determine the profile of metabolizing enzymes in both human and rodent DEC, focussing on those enzymes that are known to be involved in the activation of carcinogens. Having established this profile we will examine the ability of specific enzymes, mostly P450 isoforms, to metabolize MIO, NNAL and PhlP using the profile of metabolites and the ability to induce mutations. The ability of these carcinogens, activated by enzymes that are identified in the earlier aims, to neoplastically transform DEC will be measured. Lastly we will examine the capacity of DEC to repair different forms of DNA damage. A crucial factor in determining susceptibility might be the ability of DEC to repair DNA damage caused by the putative carcinogens. Our understanding of chemically induced pathological conditions is seriously hindered by a lack of knowledge of the ability of these cells to metabolize chemicals and to repair the genetic consequences of this activation. This proposal seeks to address some of these concerns and issues.

有令人信服的证据表明两种化学物质的作用， 烟草特有的亚硝胺和杂环胺，在诱导 人类胰腺导管腺癌。 有动物模型 对于这种涉及烟草特定亚硝胺和其他物质的癌症 涉及杂环胺的实验证据。 我们建议 检查代表性胺（2-氨基-1-甲基-6- 苯基咪唑并[4,5-b]吡啶 (PhlP) 和亚硝胺 (4- (甲基亚硝基氨基)-1-(3-吡啶基)-1-丁醇(NNAL))和致癌物质 胰管中的亚硝胺 MIP（N-亚硝基甲基（2-氧代丙基）胺） 来自人类和适当啮齿动物的上皮细胞（DEC） 物种和菌株。 我们将专注于新陈代谢的激活 这些化学物质集中于参与其作用的酶 代谢。 我们的目标是确定那些可能 使人类容易受到环境因素的胰腺营养作用 化学品并尝试定义有胰腺风险的人群 癌症诱导。 我们将确定代谢酶的概况 在人类和啮齿动物 DEC 中，重点关注那些 已知参与致癌物质的激活。 拥有 建立此概况后，我们将检查特定酶的能力， 主要是 P450 同工型，使用配置文件代谢 MIO、NNAL 和 PhlP 代谢物和诱导突变的能力。 这些能力 致癌物，由早期目标中确定的酶激活， 将测量肿瘤转化的 DEC。 最后我们将检查 DEC 修复不同形式 DNA 损伤的能力。 一个至关重要的 决定易感性的因素可能是 DEC 的修复能力 由假定的致癌物引起的 DNA 损伤。 我们对化学诱发的病理状况的理解是 由于缺乏对这些细胞能力的了解而受到严重阻碍 代谢化学物质并修复其遗传后果 激活。 该提案旨在解决其中一些问题 问题。