Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.
Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.
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DOI：
10.1371/journal.pone.0098711
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dvorak Z
中科院分区：
文献类型：
--
作者：
Novotna A;Srovnalova A;Svecarova M;Korhonova M;Bartonkova I;Dvorak Z
质子泵抑制剂奥美拉唑和兰索拉唑含有手性硫原子，它们作为外消旋体给药，即S-和R-对映异构体的等摩尔混合物。对映体纯药物埃索美拉唑和右兰索拉唑由于其改善的临床和治疗性质而被开发并引入临床实践。由于奥美拉唑和兰索拉唑是芳烃受体（AhR）的激活剂和CYP 1A基因的诱导剂，因此我们在人癌细胞和原代人肝细胞中研究了其对AhR-CYP 1A途径的对映体特异性作用。我们进行了AhR转录活性的基因报告基因测定，CYP 1A 1/2 mRNA的RT-PCR分析，CYP 1A 1/2蛋白的蛋白质印迹和CYP 1A 1/2催化活性的EROD测定。兰索拉唑和奥美拉唑对映体对AhR-CYP 1A 1/2途径的影响不同。一般而言，与较低浓度的R-对映体（即兰索拉唑为1-10 µM，奥美拉唑为10-100 µ M）相比，S-对映体是更强的AhR激活剂和CYP 1A基因诱导剂。相比之下，在较高浓度（即兰索拉唑为100 µM，奥美拉唑为250 µM）下，R-对映异构体是比S-对映异构体更强的AhR激活剂和CYP 1A诱导剂。总之，我们提供了奥美拉唑和兰索拉唑对AhR信号通路的对映体特异性作用的第一个证据。
Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1–10 µM for lansoprazole and 10–100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.
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DOI：
10.1006/bbrc.1995.1526
发表时间：
1995-04-17
影响因子：
3.1
作者：
LESCA, P;PERYT, B;HOOGENBOOM, L
通讯作者：
HOOGENBOOM, L
影响因子：
5.3
作者：
NEUHOLD, LA;SHIRAYOSHI, Y;NEBERT, DW
通讯作者：
NEBERT, DW
影响因子：
11.4
作者：
Novotna, Arleta;Petr, Pavek;Dvorak, Zdenek
通讯作者：
Dvorak, Zdenek
影响因子：
7.3
作者：
KOHL, B;STURM, E;LEACH, CA
通讯作者：
LEACH, CA
影响因子：
3.7
作者：
Vrzal R;Frauenstein K;Proksch P;Abel J;Dvorak Z;Haarmann-Stemmann T
通讯作者：
Haarmann-Stemmann T