Biopharmacy (A.M.S., M.A.R., J.S., M.H., H.K., M.F., I.S., H.E.M.), Computational Pharmacy (M.S.), and Pharmaceutical Biology (O.P.), Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Biopharmacy (A.M.S., M.A.R., J.S., M.H., H.K., M.F., I.S., H.E.M.), Computational Pharmacy (M.S.), and Pharmaceutical Biology (O.P.), Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
Mol Pharmacol. 2023 Dec 15;105(1):14-22. doi: 10.1124/molpharm.123.000725.
The pregnane X receptor (PXR) is a ligand-activated regulator of cytochrome P450 (CYP)3A enzymes. Among the ligands of human PXR is hyperforin, a constituent of St John's wort (SJW) extracts and potent inducer of human CYP3A4. It was the aim of this study to compare the effect of hyperforin and SJW formulations controlled for its content on CYP3A23-3A1 in rats. Hyperiplant was used as it contains a high hyperforin content and Rebalance because it is controlled for a low hyperforin content. In silico analysis revealed a weak hyperforin-rPXR binding affinity, which was further supported in cell-based reporter gene assays showing no hyperforin-mediated reporter activation in presence of rPXR. However, cellular exposure to Hyperiplant and Rebalance transactivated the CYP3A reporter 3.8-fold and 2.8-fold, respectively, and they induced mRNA expression in rat hepatoma cells compared with control 48-fold and 18-fold, respectively. In Wistar rats treated for 10 days with 400 mg/kg of Hyperiplant, we observed 1.8 times the mRNA expression, a 2.6-fold higher CYP3A23-3A1 protein amount, and a 1.6-fold increase in activity compared with controls. For Rebalance we only observed a 1.8-fold hepatic increase of CYP3A23-3A1 protein compared with control animals. Even though there are differing effects on r/CYP3A23-3A1 in rat liver reflecting the hyperforin content of the SJW extracts, the modulation is most likely not linked to an interaction of hyperforin with rPXR. SIGNIFICANCE STATEMENT: Treatment with St John's wort (SJW) has been reported to affect CYP3A expression and activity in rats. Our comparative study further supports this finding but shows that the pregnane X receptor-ligand hyperforin is not the driving force for changes in rat CYP3A23-3A1 expression and function in vivo and in vitro. Importantly, CYP3A induction mimics findings in humans, but our results suggest that another so far unknown constituent of SJW is responsible for the expression- and function-modifying effects in rat liver.
孕烷 X 受体 (PXR) 是细胞色素 P450 (CYP)3A 酶的配体激活调节剂。人类 PXR 的配体之一是贯叶金丝桃素，贯叶金丝桃素是圣约翰草提取物的一种成分，也是人类 CYP3A4 的有效诱导剂。本研究旨在比较贯叶金丝桃素和圣约翰草提取物配方（控制其含量）对大鼠 CYP3A23-3A1 的影响。选择 Hyperiplant 是因为它含有高含量的贯叶金丝桃素，而选择 Rebalance 是因为它的贯叶金丝桃素含量低。计算机分析显示贯叶金丝桃素与 rPXR 的结合亲和力较弱，细胞报告基因检测进一步证实，在存在 rPXR 的情况下，贯叶金丝桃素没有介导报告基因的激活。然而，细胞暴露于 Hyperiplant 和 Rebalance 分别使 CYP3A 报告基因转激活 3.8 倍和 2.8 倍，与对照相比，它们分别在大鼠肝癌细胞中诱导 mRNA 表达 48 倍和 18 倍。在用 400mg/kg Hyperiplant 处理 10 天的 Wistar 大鼠中，我们观察到 mRNA 表达增加 1.8 倍，CYP3A23-3A1 蛋白量增加 2.6 倍，活性增加 1.6 倍，与对照组相比。对于 Rebalance，与对照动物相比，我们仅观察到肝内 CYP3A23-3A1 蛋白增加 1.8 倍。尽管 SJW 提取物中贯叶金丝桃素含量的不同会对大鼠肝内 r/CYP3A23-3A1 产生不同的影响，但这种调节很可能与贯叶金丝桃素与 rPXR 的相互作用无关。意义陈述：据报道，圣约翰草 (SJW) 的治疗会影响大鼠 CYP3A 的表达和活性。我们的比较研究进一步支持了这一发现，但表明孕烷 X 受体配体贯叶金丝桃素不是体内和体外大鼠 CYP3A23-3A1 表达和功能变化的驱动力。重要的是，CYP3A 诱导与人类的发现相似，但我们的结果表明，圣约翰草的另一个目前未知的成分负责大鼠肝中表达和功能修饰的影响。
