CYP2D6 Is Inducible by Endogenous and Exogenous Corticosteroids (Retracted article. See vol. 46, pg. 1360, 2018)
CYP2D6 Is Inducible by Endogenous and Exogenous Corticosteroids (Retracted article. See vol. 46, pg. 1360, 2018)
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DOI：
10.1124/dmd.115.069229
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发表时间：
2016-05-01
影响因子：
3.9
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
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作者：
Farooq, Muhammad;Kelly, Edward J.;Unadkat, Jashvant D.
尽管根据人类肝细胞研究，细胞色素 P450 (CYP) 2D6 被广泛认为是不可诱导的，但体内数据表明它可以被内源性和外源性抗生素诱导。因此，我们研究了人类肝细胞研究中常规使用的实验条件是否可能是缺乏 CYP2D6 体外诱导的混杂因素。将夹心培养的人肝细胞 (SCHH) 在有或没有地塞米松 (100 nM) 的情况下预孵育 72 小时，然后与 1 μM 内源性（皮质醇或皮质酮）或外源性（地塞米松或泼尼松龙）皮质类固醇一起孵育。 72小时时，分别通过实时定量聚合酶链式反应、定量蛋白质组学和右美沙芬形成右啡烷对CYP2D6 mRNA、蛋白质和活性进行定量。在没有补充地塞米松的情况下，所有四种皮质类固醇均显着且稳健地诱导 CYP2D6 活性、mRNA 和蛋白质（> 10 倍）。然而，在用补充地塞米松预孵育的细胞中，这种 CYP2D6 诱导被消除。这些数据首次表明，CYP2D6 在体外是可诱导的，但培养基中常规存在的 100 nM 地塞米松掩盖了这种诱导。我们的皮质醇数据与临床观察一致，即在妊娠晚期，当皮质醇的血浆浓度增加到大约 1 μM 时，CYP2D6 可被诱导。这些发现如果在体内得到证实，将对预测 CYP2D6 介导的药物相互作用具有影响，并要求重新评估关于筛选异生素诱导 CYP2D6 的监管指南。我们的研究结果还表明，皮质醇可能是妊娠期间体内 CYP2D6 诱导的致病因素。
Although cytochrome P450 (CYP) 2D6 has been widely considered to be noninducible on the basis of human hepatocyte studies, in vivo data suggests that it is inducible by endo-and xenobiotics. Therefore, we investigated if the experimental conditions routinely used in human hepatocyte studies may be a confounding factor in the lack of in vitro induction of CYP2D6. Sandwich cultured human hepatocytes (SCHH) were preincubated with or without dexamethasone (100 nM) for 72 hours before incubation with 1 mu M endogenous (cortisol or corticosterone) or exogenous (dexamethasone or prednisolone) corticosteroids. At 72 hours, CYP2D6 mRNA, protein, and activity were quantified by real-time quantitative polymerase chain reaction, quantitative proteomics, and formation of dextrorphan from dextromethorphan, respectively. In the absence of supplemental dexamethasone, CYP2D6 activity, mRNA, and protein were significantly and robustly (> 10-fold) induced by all four corticosteroids. However, this CYP2D6 induction was abolished in cells preincubated with supplemental dexamethasone. These data show, for the first time, that CYP2D6 is inducible in vitro but the routine presence of 100 nM dexamethasone in the culture medium masks this induction. Our cortisol data are in agreement with the clinical observation that CYP2D6 is inducible during the third trimester of pregnancy when the plasma concentrations of cortisol increase to similar to 1 mu M. These findings, if confirmed in vivo, have implications for predicting CYP2D6-mediated drug-drug interactions and call for re-evaluation of regulatory guidelines on screening for CYP2D6 induction by xenobiotics. Our findings also suggest that cortisol may be a causative factor in the in vivo induction of CYP2D6 during pregnancy.