Pregnane X receptor-mediated induction of Cyp3a by black cohosh. Black cohosh (BC) is mainly used as a dietary supplement for the improvement of perimenopausal or postmenopausal symptoms, as well as other gynaecological disorders. A number of preparations made from the root of black cohosh are on the market such as Remifemin and BNO 1055. BC was originally thought to have estrogen-like action, but recent evidence failed to support this view. It was reported that black cohosh may act via the central nervous system or by interacting with oestrogen receptors with mixed agonistic (tissue-selective) and antagonistic properties. A comprehensive review of the literature on the role of black cohosh in the treatment of menopausal symptoms led to the conclusion that more studies were needed to confirm its efficacy. Side effects of black cohosh are rarely reported, however, a few individual cases of hepatotoxicity have raised safety concerns. The herbdrug interaction is also an issue in the safety of black cohosh. Cell toxicity and inhibition of CYP enzymes by black cohosh have been investigated, suggesting its clinical safety. However, in vivo studies into the safety of black cohosh are needed to determine the influence of this herb on drug metabolism and upstream mediators. 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. Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice. Lithocholic acid (LCA), the most potent endogenous chemical causing liver toxicity, is increased in patients with liver disease. LCA causes intrahepatic cholestasis, and experimental interventions to protect against LCA toxicity have been investigated using animal models. Nuclear receptors, such as pregnane X receptor, were reported to protect against LCA toxicity through regulation of CYP3A and sulfotransferase 2A that can protect from the LCA toxicity. A variety of LCA metabolites have been reported to be associated with this protection. Bile acid metabolism associated with LCA toxicity has also been investigated. LCA exposure was reported to change levels of phospholipids, cholesterol, free fatty acids, and triglycerides. However, a comprehensive view of LCA-induced alterations in endogenous metabolites has not been rigorously examined. In the current study, a change in the serum metabolome following LCA-induced liver injury was assessed in mice fed LCA-supplemented diets in order to determine the mechanism of cholestatic liver injury and to discover biomarkers for disease progression. Comparison of the LCA-induced metabolic changes and altered gene expression patterns in the farnesoid X receptor (Fxr)-null mouse that is resistant to LCA-induced liver injury provided further understanding of the mechanism of the LCA-induced liver toxicity. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl-, and linoleoyl-LPC levels after LCA exposure. LCA treatment also resulted in decreased serum sphingomyelin levels and increased hepatic ceramide levels, and induction of LPCAT and SMPD messenger RNAs (mRNAs). Transforming growth factor-beta (TGF-beta) induced Lpcat2/4 and Smpd3 gene expression in primary hepatocytes and the induction was diminished by pretreatment with the SMAD3 inhibitor SIS3. Furthermore, alteration of the LPCs and Lpcat1/2/4 and Smpd3 expression was attenuated in LCA-treated farnesoid X receptor-null mice that are resistant to LCA-induced intrahepatic cholestasis. This study revealed that LCA induced disruption of phospholipid/sphingolipid homeostasis through TGF-beta signaling and that serum LPC is a biomarker for biliary injury.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC005708-20
Application #
8348891
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2011
Total Cost
$1,105,643
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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