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51.
Hernandez JP Chapman LM Kretschmer XC Baldwin WS 《Toxicology and applied pharmacology》2006,216(2):186-196
Nonylphenol (NP) is a breakdown product of nonylphenol ethoxylates, which are used in a variety of industrial, agricultural, household cleaning, and beauty products. NP is one of the most commonly found toxicants in the United States and Europe and is considered a toxicant of concern because of its long half-life. NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s. No study to date has examined the gender-specific effects of NP on hepatic P450 expression. We provided NP at 0, 50 or 75 mg/kg/day for 7 days to male and female FVB/NJ mice and compared their P450 expression profiles. Q-PCR was performed on hepatic cDNA using primers to several CYP isoforms regulated by PXR or its relative, the constitutive androstane receptor (CAR). In female mice, NP induced Cyp2b10 and Cyp2b13, and downregulated the female-specific P450s, Cyp3a41 and Cyp3a44. In contrast, male mice treated with NP showed increased expression of Cyp2a4, Cyp2b9, and Cyp2b10. Western blots confirmed induction of Cyp2b subfamily members in both males and females. Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males. The overall increase in female-predominant P450s in males (Cyp2a4, 2b9) and the decrease in female-predominant P450s in females (Cyp3a41, 3a44) suggest that NP is in part feminizing the P450 profile in males and masculinizing the P450 profile in females. Testosterone hydroxylation was also altered in a gender-specific manner, as testosterone 16alpha-hydroxylase activity was only induced in NP-treated males. In contrast, NP-treated females demonstrated a greater propensity for metabolizing zoxazolamine probably due to greater Cyp2b induction in females. In conclusion, NP causes gender-specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females. 相似文献
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目的采用精准、可量化的方法筛选蜂胶影响PXR/CYP3A4通路调控血脂的质量标志物。方法采用人结肠癌LS174T细胞给予一定浓度的咪达唑仑注射液,同时给予不同浓度的蜂胶已知成分对照品溶液,孵育后提取样品,采用UHPLC-MS法测定生成的1′-羟基咪达唑仑含量,根据测定结果筛选出对PXR/CYP3A4通路有显著调控作用的成分,以这些成分为指标,建立同时定量方法,根据结果初步确定蜂胶中影响PXR/CYP3A4通路调控血脂代谢的质量标志物。结果所评价的蜂胶成分中,白杨素、高良姜素、异绿原酸A、槲皮素、咖啡酸苯乙酯均能够显著提高或降低1′-羟基咪达唑仑的量(与对照组和阳性对照组比较),提示上述成分能够显著影响PXR/CYP3A4表达;UHPLC-MS-MS含量测定结果显示,蜂胶中上述成分除异绿原酸A和乔松素外,均具有适宜的含量以达到显效。结论白杨素、高良姜素、咖啡酸苯乙酯和槲皮素可能是蜂胶影响PXR/CYP3A4通路调控血脂的质量标志物,且均具有抑制相关靶标表达,进而调节血脂水平的活性;同时,本研究所用质量标志物筛选、评价方法快速、高效、可量化,能够适应基于PXR/CYP3A4的大通量活性成分筛选研究。 相似文献
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Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease? 总被引:2,自引:0,他引:2
Boyer JL 《Gastroenterology》2005,129(2):735-740
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Pregnane X receptor (PXR, NR1I2) regulates the inducible expression of the 3A sub-family of cytochrome P450 genes (CYP3A). CYP3A enzymes are responsible for the oxidative metabolism of a wide array of endobiotic and xenobiotic compounds. Hepatic CYP3A gene expression is rapidly down-regulated during inflammation and sepsis. There are twelve protein kinase C (PKC) isoforms, classified into three subfamilies according to the structure of the N-terminal regulatory domain and their sensitivity to calcium and diacylglycerol. It is now well accepted that cytokine stimulation of hepatocytes increases intracellular PKC activity during inflammation and sepsis. We show here that protein kinase C alpha (PKCα) and phorbol ester-dependent PKC signaling dramatically repressed PXR activity in both, cell-based reporter gene assays and in hepatocytes. Moreover, treatment with the protein phosphatase PP1/PP2A inhibitor okadaic acid (OA) totally abolished PXR activity in reporter gene assays and in cultured hepatocytes. In mammalian two-hybrid assays, treatment with phorbol 12-myristate 13-acetate (PMA) increased the strength of interaction between PXR and the nuclear receptor co-repressor protein (NCoR). Treatment with PMA also abolished the ligand-dependent interaction between PXR and the steroid receptor co-activator 1 protein (SRC1). Our findings suggest that activation of the protein kinase C signaling pathway represses PXR activity through alterations in PXR-protein co-factor complexes, possibly through direct alterations in the phosphorylation status of one or all of these proteins. In addition, our data potentially provide important insights into the molecular mechanism of the repression of hepatic CYP3A gene expression that occurs during the inflammatory response. 相似文献
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Vitamin E activates gene expression via the pregnane X receptor 总被引:15,自引:0,他引:15
Landes N Pfluger P Kluth D Birringer M Rühl R Böl GF Glatt H Brigelius-Flohé R 《Biochemical pharmacology》2003,65(2):269-273
Tocopherols and tocotrienols are metabolized by side chain degradation via initial omega-oxidation and subsequent beta-oxidation. omega-Oxidation is performed by cytochrome P450 (CYP) enzymes which are often regulated by their substrates themselves. Results presented here show that all forms of Vitamin E are able to activate gene expression via the pregnane X receptor (PXR), a nuclear receptor regulating a variety of drug metabolizing enzymes. In HepG2 cells transfected with the human PXR and the chloramphenicol acetyl transferase (CAT) gene linked to two PXR responsive elements, CAT activity was most strongly induced by alpha- and gamma-tocotrienol followed by rifampicin, delta-, alpha- and gamma-tocopherol. The inductive efficacy was concentration-dependent; its specificity was underscored by a lower response when cotransfection with PXR was omitted. Up-regulation of endogenous CYP3A4 and CYP3A5 mRNA was obtained by gamma-tocotrienol, the most potent activator of PXR, with the same efficacy as with rifampicin. This points to a potential interference of individual forms of Vitamin E with the metabolism and efficacy of drugs. 相似文献
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