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 Cyp3a23-3a1 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 Cyp3a23-3a1 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 rCyp3a23-3a1/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.

中文翻译：

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圣约翰草制剂诱导大鼠 CYP3A23-3A1 与其金丝桃素含量无关


孕烷 X 受体 (PXR) 是细胞色素 P450 (CYP)3A 酶的配体激活调节剂。人 PXR 的配体之一是金丝桃素，它是圣约翰草 (SJW) 提取物的成分，也是人 CYP3A4 的有效诱导剂。本研究的目的是比较金丝桃素和控制其含量的SJW制剂对大鼠CYP3A23-3A1的影响。使用 Hyperiplant 是因为它含有高金丝桃素含量，而使用 Rebalance 是因为它被控制为低金丝桃素含量。计算机分析显示金丝桃素-rPXR 结合亲和力较弱，这在基于细胞的报告基因检测中得到进一步支持，显示在 rPXR 存在下没有金丝桃素介导的报告基因激活。然而，细胞暴露于 Hyperiplant 和 Rebalance 分别反式激活 CYP3A 报告基因 3.8 倍和 2.8 倍，并且与对照相比，它们分别诱导大鼠肝癌细胞中 Cyp3a23-3a1 mRNA 的表达 48 倍和 18 倍。在用 400 mg/kg Hyperiplant 治疗 Wistar 大鼠 10 天时，我们观察到与对照组相比，Cyp3a23-3a1 mRNA 表达量增加了 1.8 倍，CYP3A23-3A1 蛋白量增加了 2.6 倍，活性增加了 1.6 倍。对于 Rebalance，我们仅观察到与对照动物相比，CYP3A23-3A1 蛋白的肝脏增加了 1.8 倍。尽管 SJW 提取物中的金丝桃素含量对大鼠肝脏中的 rCyp3a23-3a1/CYP3A23-3A1 有不同的影响，但这种调节很可能与金丝桃素与 rPXR 的相互作用无关。