ROLE OF HUMAN NASAL MUCOSAL P450 IN HEAD AND NECK CANCER

人鼻粘膜 P450 在头颈癌中的作用

• 批准号: 6188552
• 负责人: Xinxin Ding
• 金额: $ 3.2万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188552
• 关键词: alleles; cancer risk; chemical carcinogen; chemical carcinogenesis; complementary DNA; cooperative study; cytochrome P450; cytotoxicity; developmental genetics; gene expression; gene frequency; genetic library; genotype; head /neck neoplasm; human fetus tissue; immunocytochemistry; isozymes; neoplasm /cancer epidemiology; neoplasm /cancer genetics; oral mucosa; perinatal; polymerase chain reaction; protein structure function; respiratory epithelium; western blottings

The long-term goal is to determine the toxic impact of environmental agents on the olfactory mucosa and neighboring head and neck organs. The specific aims for this proposal are: (1). To identify and characterize P450 gene expression in adult and fetal human nasal mucosa. The cellular distribution and developmental expression of various P450 isoforms known to be active in the metabolism of foreign compounds will be examined, including CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 3A4, 3A5, 3A7, and 4B1. These studies will broaden our knowledge of the molecular basis for risk assessment of potential toxicants in humans and may have implications in the vulnerability of the nasal tissue in the perinatal period. (2). To determine whether patients with nasal tumor or other head and neck cancer have a lower frequency of defective CYP2A6 alleles than a control population. This pilot molecular epidemiological study will test the hypothesis that CYP2A6, a tissue-selective P450 gene known to be expressed in human nasal mucosa and active in the metabolic activation of numerous procarcinogens, plays an important role in the chemical carcinogenesis in the nasal cavity and neighboring organs, including the pharynx, larynx, and the oral cavity, where toxic metabolites formed in the nasal mucosa can be transported. Consequently, individuals with defective CYP2A6 alleles would have a lower risk of developing head and neck cancer. Confirmation of this hypothesis could provide a basis for future chemoprevention efforts using CYP2A6 inhibitors. The outcome of this study will contribute significantly toward a molecular approach to human risk assessment, which is also the goal of the parent grant.

长期目标是确定环境药物对嗅觉粘膜和邻近的头部和颈部器官的毒性影响。 该提案的具体目的是：（1）。识别和表征成人和胎儿人鼻粘膜中P450基因的表达。 将检查各种p450同工型的细胞分布和发育表达，已知在外国化合物的代谢中活跃，包括CYP1A1，1A2、1B1、1B1、2A6、2B6、2B6、2C8、2C9、2C18、2C18、2C19、2C19、2D6、2D6、2E1、2E1、2E1、2F1、3AA44、3Aa4、3Aa4、3Aa77。 这些研究将扩大我们对人类潜在毒物风险评估的分子基础的了解，并可能对围产期鼻组织的脆弱性产生影响。 （2）。确定鼻肿瘤或其他头颈癌患者的CYP2A6等位基因的频率低于对照人群。 这项试验性分子流行病学研究将检验以下假说：CYP2A6是一种已知的组织选择性的p450基因，该基因在人类鼻粘膜中表达并活跃于许多procarcinogens的代谢激活中，在鼻腔腔和邻居的pharyx and pharynx中起着重要作用，在化学癌中起着重要作用。在鼻粘膜中形成的代谢产物可以运输。 因此，CYP2A6等位基因缺陷的个体患头和颈部癌的风险较低。 对该假设的确认可以为使用CYP2A6抑制剂的未来化学预订工作提供基础。这项研究的结果将对人类风险评估的分子方法产生重大贡献，这也是父母赠款的目标。