Hernandez Juan P, Huang Wendong, Chapman Laura M, Chua Steven, Moore David D, Baldwin William S
Biological Sciences, The University of Texas at El Paso, El Paso, Texas 79968, USA.
Toxicol Sci. 2007 Aug;98(2):416-26. doi: 10.1093/toxsci/kfm107. Epub 2007 May 5.
Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription-PCR of Cyp2b10 transcript levels. CAR-null (CAR -/-) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.
壬基酚（NP）及其母体化合物壬基酚聚氧乙烯醚是在美国水道中发现的一些最普遍的化学物质。NP还具有抗生物降解性，并且是一种已知的环境雌激素，这使得NP成为一种令人关注的化学物质。我们的数据表明，NP还能激活组成型雄甾烷受体（CAR），这是一种在诱导解毒酶（包括细胞色素P450s）中起重要作用的孤儿核受体。反式激活分析表明，NP可增加小鼠CAR（mCAR）的转录活性，并且NP处理可克服反向激动剂雄甾醇对mCAR激活的抑制作用。用50或75mg/kg/天的NP处理野生型（CAR +/+）小鼠，通过蛋白质免疫印迹法显示Cyp2b蛋白表达呈剂量依赖性增加，并通过Cyp2b10转录水平的定量逆转录PCR得到证实。CAR基因敲除（CAR -/-）小鼠在NP处理后未显示Cyp2b表达增加，表明CAR是NP介导的Cyp2b诱导所必需的。此外，NP增加了CAR向细胞核的转位，这是CAR转录活性开始的关键步骤。NP还可诱导原代人肝细胞中的CYP2B6，并增加人源化CAR小鼠中Cyp2b10信使RNA和蛋白质的表达，表明NP也是人CAR 的激活剂。总之，NP是一种CAR激活剂，这在体外通过反式激活分析以及在体内通过转基因CAR小鼠模型得到了证实。
