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首页> 外文期刊>Biochemical Pharmacology >Down-regulation of phenobarbital-induced cytochrome P4502B mRNAs and proteins by endotoxin in mice: independence from nitric oxide production by inducible nitric oxide synthase.
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Down-regulation of phenobarbital-induced cytochrome P4502B mRNAs and proteins by endotoxin in mice: independence from nitric oxide production by inducible nitric oxide synthase.

机译:小鼠内毒素的苯甲虫诱导的细胞色素P4502B mRNA和蛋白质的下调:诱导型一氧化氮合酶的一氧化氮产生的独立性。

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摘要

Multiple hepatic cytochrome P450 enzymes are down-regulated at the mRNA and protein levels during inflammation and infection. A body of evidence suggests that nitric oxide (NO) produced from inducible NO synthase (NOS2) is responsible for some of these effects. The current study was designed to examine the NO dependencies of the down-regulation of phenobarbital-induced CYP2B mRNAs and proteins by bacterial endotoxin (lipopolysaccharide, LPS) treatment in vivo, using an NOS2-null mouse model. Treatment of C57/BL6 mice with 0.3mg/kg of LPS maximally suppressed phenobarbital-induced CYP2B9 and 2B10 mRNAs measured 12hr after injection, whereas 1-10mg/kg of LPS was required to elevate NO production. Down-regulation of CYP2B mRNAs by 1mg/kg of LPS was equivalent in wild-type and NOS2-null mice. No effect of LPS in the dose range of 0.3 to 10mg/kg was observed on microsomal CYP2B protein levels measured 12hr after treatment, whereas 1mg/kg of LPS suppressed CYP2B proteins 24hr after treatment in both wild-type and NOS2-null mice. We conclude that the main mechanism for the down-regulation of CYP2B proteins in mouse liver following moderate- or high-dose LPS treatment is via NO-independent suppression of CYP2B9 and 2B10 mRNAs. Unlike rat hepatocytes, the contribution of a rapid, NO-dependent mechanism of CYP2B protein suppression in mouse liver appears to be minor or non-existent.
机译:在炎症和感染期间,多种肝细胞色素P450酶在mRNA和蛋白质水平下进行下调。证据表明,由诱导型没有合酶(NOS2)产生的一氧化氮(NO)负责其中一些效果。目前的研究旨在使用NOS2-NULL鼠标模型在体内进行细菌内毒素(脂多糖,LPS)处理来检查苯甲虫诱导的CYP2B mRNA和蛋白质的下调的依赖性。用0.3mg / kg的LPS处理C57 / BL6小鼠最大抑制的苯巴罗诱导的CYP2B9和2B10mRNA测量12小时后测量12小时,而1-10mg / kg LPS需要升高生产。通过野生型和NOS2-禁止小鼠的1mg / kg LPS对CYP2B MRNA的下调。在治疗后12小时测量的微粒体CYP2B蛋白水平上观察到LPS在0.3至10mg / kg的剂量范围内的影响,而在野生型和NOS2-核小鼠中处理后,1mg / kg LPS抑制了CYP2B蛋白24Hr。我们得出结论,在中等或高剂量LPS​​处理之后小鼠肝脏治疗中CYP2B蛋白对CYP2B蛋白进行下调的主要机制是通过无关抑制CYP2B9和2B10mRNA。与大鼠肝细胞不同,CYP2B蛋白抑制在小鼠肝脏中快速,无依赖机制的贡献似乎是轻微或不存在的。

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