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Oleanolic Acid-Mediated Inhibition of Pregnane X Receptor and Constitutive Androstane Receptor Attenuates Rifampin-Isoniazid Cytotoxicity
journal contribution
posted on 2017-09-25, 12:33 authored by Yen-Ning Lin, Chao-Jung Chen, Hsiao-Yun Chang, Wai-Kok Cheng, Ying-Ray Lee, Jih-Jung Chen, Yun-Ping LimInteractions 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.