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
Wang, Yongtao; Chen, Yixin; Guan, Lihuan et al. (2018) Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming. Cell Death Differ 25:733-746
Zhao, Jie; Xie, Cen; Mu, Xiyan et al. (2018) Metabolic alterations in triptolide-induced acute hepatotoxicity. Biomed Chromatogr 32:e4299
Qin, Zifei; Li, Shishi; Yao, Zhihong et al. (2018) Metabolic profiling of corylin in vivo and in vitro. J Pharm Biomed Anal 155:157-168
Qin, Zifei; Li, Shishi; Yao, Zhihong et al. (2018) Chemical inhibition and stable knock-down of efflux transporters leads to reduced glucuronidation of wushanicaritin in UGT1A1-overexpressing HeLa cells: the role of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs Food Funct 9:1410-1423
Nair, Sneha G; Patel, Daxesh P; Gonzalez, Frank J et al. (2018) Simultaneous determination of etonogestrel and ethinyl estradiol in human plasma by UPLC-MS/MS and its pharmacokinetic study. Biomed Chromatogr 32:e4165
Madeen, Erin P; Löhr, Christiane V; You, Hannah et al. (2017) Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice. Mol Carcinog 56:163-171
Cai, Jingwei; Zhang, Jingtao; Tian, Yuan et al. (2017) Orthogonal Comparison of GC-MS and 1H NMR Spectroscopy for Short Chain Fatty Acid Quantitation. Anal Chem 89:7900-7906
Patel, Daxesh P; Krausz, Kristopher W; Xie, Cen et al. (2017) Metabolic profiling by gas chromatography-mass spectrometry of energy metabolism in high-fat diet-fed obese mice. PLoS One 12:e0177953
Patel, Dhaval; Thompson, Matthew D; Manna, Soumen K et al. (2017) Unique and Novel Urinary Metabolomic Features in Malignant versus Benign Adrenal Neoplasms. Clin Cancer Res 23:5302-5310
Hong, Xiaodan; Zheng, Yuanru; Qin, Zifei et al. (2017) In Vitro Glucuronidation of Wushanicaritin by Liver Microsomes, Intestine Microsomes and Expressed Human UDP-Glucuronosyltransferase Enzymes. Int J Mol Sci 18:

Showing the most recent 10 out of 215 publications