4-nonylphenol alters P-450 expression in the liver

说明(申请人提供)：壬基酚(NP)是壬基酚聚氧乙烯醚的降解产物。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，当存在时，通常是浓度最高的污染物。此外，NP是唯一一种在废物污泥中发现的化学物质，超过70%的时间超过建议的限度。NP在美国和欧洲无处不在的原因是因为它是一种高用途的化学品，耐生物降解。这使得NP成为令人担忧的毒药。NP的毒物-毒物和药物-毒物相互作用尚不清楚。药物不良反应很常见，大多数原因尚不清楚。接触NP等环境化学品可能会增加药物的不良反应。NP激活孕烷X受体(PXR)，我们的数据表明它激活组成雄烷的受体(CAR)。这些核受体在调节Cyp2b和CypSa的表达方面很重要；这两个P450经常涉及药物不良反应。此外，我们的数据表明，NP会引起性别特异性的P450诱导，因此，与女性相比，暴露于NP可能会对男性产生不同的药理和毒理效应。总之，认识到导致P450的职业和环境危害并增加潜在的药物-药物相互作用可以导致替代的药理策略，并最终拯救生命。本研究的目的是(1)确定NP是否以性别特异性的方式诱导P450；(2)检测NP是否通过激活CAR来诱导药物代谢的P450(Cyps)；(3)检测P450诱导的药理学意义。

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.