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首页> 外文期刊>Journal of pharmaceutical sciences. >Acute exposure to doxorubicin results in increased cardiac P-glycoprotein expression.
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Acute exposure to doxorubicin results in increased cardiac P-glycoprotein expression.

机译:急性暴露于阿霉素会导致心脏P-糖蛋白表达增加。

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摘要

Doxorubicin is a frequently used anticancer drug, but its use is restricted due to the occurrence of severe side effects, namely strong cardiotoxicity. It is known from cancer cells that doxorubicin enhanced the expression of its efflux pump P-glycoprotein (P-gp), which may modulate local drug concentrations. We therefore studied the cardiac expression of P-gp in doxorubicin-treated mice. Mice were treated with doxorubicin, and P-gp expression was studied after 1, 3, and 5 days. Thereby, we could show a significant upregulation of abcb1a (162 +/- 15% of control) and abcb1b (418 +/- 110% of control) mRNA transcripts after 3 days. On protein level, western blot analysis and immunofluorescence staining revealed a similar finding 5 days after doxorubicin administration. In addition, these results could be confirmed by in vitro models using primary rat cardiomyocytes and the murine cardiomyocyte-like HL-1 cells. Besides an enhanced mRNA and protein expression, doxorubicin-treated HL-1 cells also demonstrated an enhanced P-gp function as assessed by a daunorubicin accumulation assay. Our in vivo and in vitro results demonstrate a cardiac upregulation of P-gp in doxorubicin-treated mice on expression and functional level. This finding may be relevant for cardiac tissue concentrations of P-gp substrates and may represent a mechanism in cardiac self-protection against xenobiotics.
机译:阿霉素是一种常用的抗癌药物,但由于发生严重的副作用即强心脏毒性,因此其使用受到限制。从癌细胞中知道,阿霉素可增强其外排泵P-糖蛋白(P-gp)的表达,这可能会调节局部药物浓度。因此,我们研究了阿霉素处理的小鼠中P-gp的心脏表达。用阿霉素处理小鼠,并在1、3和5天后研究P-gp表达。因此,我们可以显示3天后abcb1a(对照组162 +/- 15%)和abcb1b(对照组418 +/- 110%)mRNA转录显着上调。就蛋白质水平而言,阿霉素给药5天后,蛋白质印迹分析和免疫荧光染色显示了相似的发现。此外,这些结果可以通过使用原代大鼠心肌细胞和鼠类心肌细胞样HL-1细胞的体外模型得到证实。通过柔红霉素累积测定法评估,除了增强的mRNA和蛋白质表达外,经阿霉素处理的HL-1细胞还表现出增强的P-gp功能。我们的体内和体外结果表明,阿霉素处理的小鼠的P-gp在表达和功能水平上均呈心脏上调。该发现可能与心脏组织中P-gp底物的浓度有关,并且可能代表了心脏针对外源生物的自我保护机制。

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