Oleanolic Acid-Mediated Inhibition of Pregnane X Receptor and Constitutive Androstane Receptor Attenuates Rifampin-Isoniazid Cytotoxicity

• Published in: Journal of agricultural and food chemistry Vol. 65; no. 39; pp. 8606 - 8616
• Main Authors: Lin, Yen-Ning, Chen, Chao-Jung, Chang, Hsiao-Yun, Cheng, Wai-Kok, Lee, Ying-Ray, Chen, Jih-Jung, Lim, Yun-Ping
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.10.2017
• Subjects: adverse effects; antagonists; catalytic activity; Cell Line; cytochrome P-450; Cytochrome P-450 CYP2B6 - genetics; Cytochrome P-450 CYP2B6 - metabolism; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - pharmacology; cytotoxicity; Drug Interactions; drugs; Gene Expression Regulation, Enzymologic - drug effects; Hep G2 Cells; Hepatocytes - drug effects; Humans; isoniazid; Isoniazid - toxicity; oleanolic acid; Oleanolic Acid - pharmacology; probability; Promoter Regions, Genetic - drug effects; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Steroid - antagonists & inhibitors; rifampicin; Rifampin - toxicity; rodents; Species Specificity; transcription (genetics); transcriptional activation; pregnane X receptor; isoniazid; cytochrome P450; constitutive androstane receptor; oleanolic acid; rifampin
• ISSN: 0021-8561; 1520-5118; 1520-5118
• DOI: 10.1021/acs.jafc.7b02696

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.