4-nonylphenol alters P-450 expression in the liver

4-壬基酚改变肝脏中 P-450 的表达

• 批准号: 7229655
• 负责人: Juan P Hernandez
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229655
• 关键词: 4-nonylphenol; Animals; Binding; Biodegradation; Biological Assay; Cells; Chemicals; Cytochrome P450; Data; Development; Drug Interactions; Environmental Estrogen; Environmental Hazards; Environmental Pollution; Environmental sludge; Enzymes; Europe; Exposure to; Family member; Female; Gender; Genetic Transcription; Goals; Health; Human; In Vitro; Individual; Knockout Mice; Lead; Length; Life; Liver; Measures; Mediating; Mouse Strains; Mus; Nuclear Receptors; Occupational; Orphan; Paralysed; Personal Satisfaction; Pharmaceutical Preparations; Phase; Polymerase Chain Reaction; Proteins; Reaction; Reporter Genes; Resistance; Role; Staging; Surveys; Testing; Time; Transgenic Mice; United States; Water; Western Blotting; Xenobiotics; Zoxazolamine; chemical elimination; constitutive androstane receptor; day; detoxication; environmental chemical; in vivo; male; member; nonylphenol; nonylphenol ethoxylate; nuclear receptor subfamily 1, group I, member 3, human; pregnane X receptor; sex; toxicant; toxicant interaction; treatment duration; wasting

DESCRIPTION (provided by applicant): Nonylphenol (NP) is a degradation product of the nonylphenol ethoxylates. The United States Geological Survey showed that NP is one of the top 7 most commonly found organic environmental contaminants in water, and when present, is usually the contaminant found at the highest concentration. Furthermore, NP is the only chemical found more than 70% of the time above suggested limits in waste sludges. The reason NP is ubiquitous throughout the United States and Europe is because it is a high use chemical resistant to biodegradation. This makes NP a toxicant of concern. NP's toxicant-toxicant and drug-toxicant interactions are unknown. Adverse drug reactions are common, and the cause of most is unknown. Exposure to environmental chemicals such as NP may increase adverse drug reactions. NP activates the pregnane X-receptor (PXR) and our data suggests it activates the constitutive androstane receptor (CAR). These nuclear receptors are important in regulating the expression of Cyp2b and CypSa; two P450s often involved in adverse drug reactions. Furthermore, our data indicates that NP causes gender specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females. In summary, recognition of the occupational and environmental hazards that induce P450s and increase potential drug-drug interactions can lead to alternative pharmacological strategies and ultimately save lives. The goal of this study is to (1) determine whether NP induces P450s in a gender-specific manner, (2) test whether NP induces the drug-metabolizing P450s (CYPs) by activating CAR, and (3) test the pharmacological significance of P450 induction.

描述（由申请人提供）： 壬基酚（NP）是壬基酚乙氧基化物的降解产物。美国地质调查局显示，NP 是水中最常见的 7 种有机环境污染物之一，并且当存在时，通常是浓度最高的污染物。此外，NP 是唯一一种在废污泥中超过建议限值 70% 以上的化学物质。 NP 在美国和欧洲普遍存在的原因是它是一种高用途的抗生物降解化学品。这使得 NP 成为令人担忧的毒物。 NP 的毒物与毒物以及药物与毒物之间的相互作用尚不清楚。药物不良反应很常见，而且大多数的原因尚不清楚。接触NP等环境化学物质可能会增加药物不良反应。 NP 激活孕烷 X 受体 (PXR)，我们的数据表明它激活组成型雄甾烷受体 (CAR)。这些核受体对于调节 Cyp2b 和 CypSa 的表达非常重要；两个P450经常参与药物不良反应。此外，我们的数据表明，NP 会引起性别特异性 P450 诱导，因此与女性相比，接触 NP 可能会对男性产生不同的药理和毒理学作用。总之，认识到诱发 P450 并增加潜在药物间相互作用的职业和环境危害可以导致替代药理学策略并最终挽救生命。本研究的目的是（1）确定 NP 是否以性别特异性方式诱导 P450，（2）测试 NP 是否通过激活 CAR 诱导药物代谢 P450（CYP），以及（3）测试 NP 的药理学意义P450感应。