4-nonylphenol alters P-450 expression in the liver

描述（由申请人提供）：壬基酚（NP）是壬基酚聚氧乙烯酯的降解产物。美国地质调查局显示，NP是水体中最常见的七大有机环境污染物之一，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发现超过建议限值70%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耐生物降解的化学物质。这使得NP成为一种值得关注的有毒物质。NP的毒性-毒性和药物毒性相互作用尚不清楚。药物不良反应是常见的，大多数原因尚不清楚。暴露于环境化学物质如NP可能会增加药物不良反应。NP激活妊娠x受体（PXR），我们的数据表明它激活构成型雄甾受体（CAR）。这些核受体在调节Cyp2b和CypSa的表达中起重要作用；两种p450常与药物不良反应有关。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学和毒理学效应。总之，认识到诱发p450的职业和环境危害，并增加潜在的药物-药物相互作用，可以导致替代的药物策略，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)检测NP是否通过激活CAR诱导药物代谢P450 (CYPs);(3)检测诱导P450的药理意义。

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.