Pregnane X receptor-mediated induction of Cyp3a by black cohosh

Abstract

Black cohosh (BC) has been widely applied for the treatment of menopausal symptoms. However, increasing concerns about herb–drug interactions demand the need for studies on the influence of BC on cytochrome 450. Cyp3a11 in liver was induced by 7-fold in wild-type mice treated with 500 mg/kg black cohosh for 28 days compared with the control group as assessed by quantitative real-time PCR; no difference was found in small intestine and kidney, suggesting that up-regulation of Cyp3a11 by black cohosh was liver-specific. Western blot, activity assays, and pharmacokinetic analyses established dose- and time-dependent induction of Cyp3a11. To determine the mechanism of Cyp3a11 induction, including the role of pregnane X receptor (PXR) in vivo and in vitro, respectively, in Pxr-null, PXR-humanized, and double transgenic CYP3A4/hPXR mice, cell-based luciferase assays were employed revealing that mouse PXR played a direct role in the induction of Cyp3a11; human PXR was not activated by black cohosh. Overall, these findings demonstrate that induction of Cyp3a11 is liver-specific and involved only mouse PXR, not the human counterpart. Thus, the incidence of herb–drug interaction in patients administered black cohosh may not be mediated by human PXR and CYP3A4.

Keywords::

• Pregnane X receptor
• CYP3A
• black cohosh
• pregnenolone 16α-carbonitrile
• midazolam

Acknowledgements

We thank Steven A. Kliewer for the Pxr-null mice and John Buckley and Yan Cai for help with the animal studies.

Declaration of interest

This work was supported by the National Cancer Institute Intramural Research Program. Xiaoyan Pang was partially supported by a fellowship from China Scholarship Council.