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首页> 外文期刊>The Journal of toxicological sciences >Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity
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Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity

机译：诱导沙利度胺培养胎盘细胞中的人细胞色素P450 3A酶，与生物活化和毒性相关性

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摘要

Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of thalidomide due to oxidation to 5-hydroxythalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1 '- and 4-hydroxylation and thalidomide 5-hydroxylation activities. Human placental BeWo cells, cultured in the recommended media, also indicated detectable midazolam 1 '- and 4-hydroxylation and thalidomide 5-hydroxylation activities. To reduce any masking effects by endogenous hormones used in the recommended media, induction of P450 3A4/5 mRNA and oxidation activities were measured in placental BeWo cells cultured with a modified medium containing 5% charcoal-stripped fetal bovine serum. Thalidomide significantly induced P450 3A4/5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold, but rifampicin only enhanced P450 3A5 and PXR mRNA under the modified media conditions. Under these modified conditions, thalidomide also significantly induced midazolam 1 '-hydroxylation and thalidomide 5-hydroxylaion activities 3-fold but not bupropion hydroxylation activity. Taken together, activation of thalidomide to 5-hydroxythalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.
机译：由于氧化至5-羟基硫化物和随后的肝脏代谢活化，已经介绍了自动诱导的人细胞色素P450 3A酶参与沙利度胺的致畸性和临床结果的证据。在该研究中，更相关的人胎盘制剂和胎盘Bewo细胞显示出低但可检测的P450 3A4 / 5 mRNA表达和药物氧化活性。来自三个受试者的人胎盘微粒体级分显示可检测的咪达唑仑1' - 和4-羟基化和沙利度胺5-羟基化活性。人体胎盘Bewo细胞，在推荐介质中培养，也表明了咪达唑仑1'和4-羟基化和沙利度胺5-羟基化活性。为了通过推荐介质中使用的内源激素减少任何掩蔽效果，在用含有5％炭剥离的胎儿牛血清的改性培养基培养的胎盘Bewo细胞中测量P450 3A4 / 5 mRNA和氧化活性的诱导。沙利度胺显着诱导P450 3A4 / 5,2B6和妊娠X受体（PXR）mRNA水平2至3倍，但在修饰的介质条件下仅增强P450 3A5和PXR mRNA的利福平。在这些改性条件下，沙利度胺也显着诱导咪达唑仑1' - 羟基化和沙利度胺5-羟基激活3倍但不是缓冲羟基化活性。在体内提出，在人胎盘和人胎盘中的P450 3A酶的自动化激活沙利度胺至5-羟基硫代胺的激活，以及肝脏。

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