Pregnane X receptor-mediated induction of Cyp3a by black cohosh.
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.
Pang
Xiaoyan
X
Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, People's Republic of China.
Cheng
Jie
J
Krausz
Kristopher W
KW
Guo
De-an
DA
Gonzalez
Frank J
FJ
D000818:Animals; D015153:Blotting, Western; D031885:Cimicifuga / Q000737:chemistry* / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D057075:Enzyme Assays; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000494:pharmacology* / Q000633:toxicity; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012503:Saponins / Q000737:chemistry / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000378:metabolism
D008565:Membrane Proteins; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D012503:Saponins; D014315:Triterpenes; C457248:23-epi-26-deoxyactein; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C096064:actein; D008874:Midazolam