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）：Nonylphenol（NP）是乙氧基甲氧基的降解产物。美国的地质调查表明，NP是水中最常见的7个有机环境污染物之一，当存在时，通常是最高浓度的污染物。此外，NP是唯一在上述时间限制废物污泥中唯一发现超过70％的化学物质。 NP在整个美国和欧洲无处不在的原因是因为它是对生物降解的高使用耐化学性。这使得NP成为关注的毒性。 NP的毒性毒性和药物毒性相互作用尚不清楚。不良药物反应很常见，大多数原因是未知的。暴露于环境化学物质（例如NP）可能会增加不良药物反应。 NP激活妊娠X受体（PXR），我们的数据表明它激活了本构雄烷受体（CAR）。这些核受体对于调节CYP2B和CYPSA的表达很重要。两个P450通常涉及不良药物反应。此外，我们的数据表明，与女性相比，NP会导致性别特定的P450诱导，因此接触NP可能会在男性中引起明显的药理和毒理学作用。总而言之，认识到诱发P450并增加潜在药物相互作用的职业和环境危害可以导致替代性药理策略，并最终挽救生命。这项研究的目的是（1）确定NP是否以性别特异性诱导P450，（2）测试NP是否通过激活CAR来诱导药物代谢P450（CYP），以及（3）测试P450诱导的药理意义。