Interactions between transcriptional inducers of cytochrome P450 (CYP450) and pharmacological agents might decrease drug efficacy and induce side effects. Such interactions could be prevented using an antagonist of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Here, we aimed to determine the antagonistic effect of oleanolic acid (OA) on PXR and CAR. OA attenuated the promoter activities, expressions, and enzyme catalytic activities of CYP3A4 and CYP2B6 mediated by rifampin (RIF) and CITCO. Moreover, OA displayed species specificity for rodent PXR. Interaction of coregulators with PXR and transcriptional complexes on the CYP3A4 promoter was disrupted by OA. Additionally, OA reversed the cytotoxic effects of isoniazid induced by RIF. These data demonstrate that OA inhibited the transactivation of PXR and CAR, reduced the expression and function of CYP3A4 and CYP2B6, and may therefore serve as an effective agent for reducing probability adverse interactions between transcriptional inducers of CYP450 and therapeutic drugs.

中文翻译：

---

齐墩果酸介导的孕烷X受体和组成型雄甾烷受体的抑制作用减弱利福平-异烟肼的细胞毒性。

细胞色素P450（CYP450）转录诱导剂与药理剂之间的相互作用可能会降低药物疗效并诱发副作用。使用孕烷X受体（PXR）和组成型雄甾烷受体（CAR）的拮抗剂可以防止此类相互作用。在这里，我们旨在确定齐墩果酸（OA）对PXR和CAR的拮抗作用。OA减弱了利福平（RIF）和CITCO介导的CYP3A4和CYP2B6的启动子活性，表达和酶催化活性。此外，OA显示出对啮齿动物PXR的物种特异性。CYP3A4上coregulators与PXR和转录复合物的相互作用启动子被OA破坏。另外，OA逆转了RIF诱导的异烟肼的细胞毒性作用。这些数据证明OA抑制PXR和CAR的反式激活，降低CYP3A4和CYP2B6的表达和功能，因此可以作为降低CYP450转录诱导剂与治疗药物之间不良相互作用的可能性的有效药物。