Human CYP2A and respiratory tract xenobiotic toxicity

人类 CYP2A 和呼吸道外源性毒性

• 批准号: 8430140
• 负责人: Xinxin Ding
• 金额: $ 37.02万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430140
• 关键词: 7alpha hydroxylase; A/J Mouse; Abbreviations; Air; Animal Model; Area; Aryl Hydrocarbon Hydroxylases; Biological Assay; Butanones; Cancer Etiology; Carcinogenicity Tests; Carcinogens; Cessation of life; Chemoprevention; Cytochrome P450; DNA Adducts; DNA Damage; Dose; Enzymes; Extrahepatic; Family; Future; Goals; Hepatic; Hepatic Tissue; Hepatocyte; Human; Incidence; Individual; Knockout Mice; Laboratories; Lead; Liver; Lung; Lung Neoplasms; Mainstreaming; Malignant neoplasm of lung; Mediating; Metabolic Activation; Metabolic Biotransformation; Methods; Modeling; Monitor; Mus; NADPH-Ferrihemoprotein Reductase; Outcome; Particulate; Pathway interactions; Play; Predictive Value; Protocols documentation; Research; Respiratory System; Respiratory tract structure; Risk; Rodent; Role; Smoke; Smoking Prevention; Structure of parenchyma of lung; Testing; Tissues; Tobacco; Tobacco-Associated Carcinogen; Toxic effect; Transgenic Mice; Wild Type Mouse; Women' s Group; Xenobiotics; adduct; base; cigarette smoke-induced; cigarette smoking; cigarette smoking; efficacy testing; environmental chemical; enzyme activity; improved; in vivo; liquid chromatography mass spectrometry; lung carcinogenesis; lung tumorigenesis; men' s group; mouse model; novel; novel strategies; parent grant; response; safety testing; selective expression; tobacco control; toxicant; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The research goal of this revision proposal is related to Reducing Toxicity of Tobacco Products and Smoke, one of the four areas relevant to the Family Smoking Prevention and Tobacco Control Act. Specifically, we seek to gain a better understanding of the mechanisms underlying cigarette smoke (CS)-induced lung tumorigenesis in mouse models, in order to improve the utility of mouse models for testing the carcinogenicity of tobacco products. We propose to use two novel transgenic mouse models developed in the PI's laboratory to test the hypotheses that 1) suppression of hepatic cytochrome P450 (P450) family of biotransformation enzyme activity will lead to increased circulating and tissue levels of CS carcinogens and, consequently, increased lung DNA damage and tumorigenesis in mice exposed chronically to CS, and 2) CS-induced lung tumorigenesis depends on target-tissue bioactivation of tobacco carcinogens by P450 enzymes. The two mouse models, both targeting the cytochrome P450 reductase (CPR), an enzyme required for the activities of all microsomal P450 enzymes, are the liver-Cpr-null (LCN) mouse, in which Cpr expression is absent in hepatocytes, and the extra-hepatic Cpr-low (or xh-CL) mouse, in which Cpr expression, and thus P450 activities, in all extrahepatic tissues (including the lung) are greatly decreased. Two Specific Aims are proposed. In Aim 1, we will determine the impact of hepatic P450 activity on CS-induced lung tumorigenesis. We will compare LCN A/J and wild-type (WT) A/J mice for sensitivity to CS-induced lung tumorigenesis, and for levels of CS-induced lung DNA adducts formed by major tobacco carcinogens in vivo. The ability to show increased tumorigenic responses in tumor bioassays would make it more practical to apply the assays to testing of new "reduced-toxicity" tobacco products, as well as for testing efficacy of lung tumor chemoprevention. In Aim 2, we will determine whether CS-induced lung tumorigenesis in AJ mouse depends on P450-mediated bioactivation in the target tissue. We will compare xh-CL A/J and WT A/J mice for sensitivity to CS-induced lung tumorigenesis, and for levels of CS-induced DNA adducts in the lungs and livers. The anticipated results will resolve the controversy about whether the lung tumors observed in CS-exposed mouse models are derived from direct tumor initiation by CS, through genotoxic pathways that depend on P450- mediated bioactivation of procarcinogens, as opposed to increased promotion by CS of spontaneous tumors. PUBLIC HEALTH RELEVANCE: A better understanding of the mechanisms underlying the cigarette smoke-induced lung tumorigenesis in the mouse would increase confidence in the predictive value of the animal model for the human risks of developing lung cancer, which is the leading cause of cancer-related death in the U.S. General improvements in the sensitivity of the mouse models to cigarette smoke-induced lung tumorigenesis would make mouse lung tumor bioassays more applicable to the testing of various "reduced-toxicity" tobacco products, as well as for testing efficacy of lung tumor chemoprevention.

描述（由申请人提供）：本修订提案的研究目标与降低烟草制品和烟雾的毒性有关，这是与《家庭吸烟预防和烟草控制法》相关的四个领域之一。具体而言，我们试图获得更好的了解香烟烟雾（CS）诱导的小鼠模型肺肿瘤发生的机制，以提高小鼠模型的实用性，用于测试烟草制品的致癌性。我们建议使用PI实验室开发的两种新型转基因小鼠模型来验证以下假设：1）抑制肝细胞色素P450（P450）家族的生物转化酶活性将导致循环和组织中的 CS致癌物，因此，增加肺DNA损伤和肿瘤发生在小鼠长期暴露于CS，和2）CS诱导的肺肿瘤发生依赖于靶组织的生物激活烟草致癌物的P450酶。两种小鼠模型均靶向细胞色素P450还原酶（CPR）（一种所有微粒体P450酶活性所需的酶），分别为肝-Cpr-null（LCN）小鼠（肝细胞中不存在Cpr表达）和肝外Cpr-low（肝外Cpr-低）小鼠（肝细胞中不存在Cpr表达）。（或xh-CL）小鼠，其中所有肝外组织（包括肺）中的Cpr表达以及因此P450活性大大降低。提出了两个具体目标。在目的1中，我们将确定肝脏P450活性对CS诱导的肺肿瘤发生的影响。我们将比较LCN A/J和野生型（WT）A/J小鼠对CS诱导的肺肿瘤发生的敏感性，以及体内主要烟草致癌物形成的CS诱导的肺DNA加合物的水平。在肿瘤生物测定中显示出增加的致瘤反应的能力将使该测定更实际地应用于测试新的“毒性降低”的烟草产品，以及用于测试肺肿瘤化学预防的功效。目的2：研究CS诱导的AJ小鼠肺肿瘤发生是否依赖于靶组织中P450介导的生物激活。我们将比较xh-CL A/J和WT A/J小鼠对CS诱导的肺肿瘤发生的敏感性，以及肺和肝脏中CS诱导的DNA加合物的水平。预期的结果将解决的争议，是否在CS暴露的小鼠模型中观察到的肺肿瘤是来自直接肿瘤启动CS，通过遗传毒性途径，依赖于P450介导的生物激活的原致癌物，而不是增加促进CS的自发性肿瘤。 公共卫生相关性：更好地理解小鼠中香烟烟雾诱导的肺肿瘤发生的机制将增加对动物模型预测人类患肺癌风险价值的信心，这是美国癌症相关死亡的主要原因。小鼠模型对香烟烟雾敏感性的总体改善-诱导的肺肿瘤发生将使小鼠肺肿瘤生物测定更适用于测试各种“毒性降低”的烟草产品，以及用于测试肺肿瘤化学预防的功效。