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      Panax ginseng Inhibits Metabolism of Diester Alkaloids by Downregulating CYP3A4 Enzyme Activity via the Pregnane X Receptor

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          Abstract

          To investigate the effects of P. ginseng C.A. Mey ( P. ginseng) on the metabolism of diester alkaloids and explore the potential mechanism. P. ginseng was administered orally to rats for 7 days, after which liver microsome samples were prepared and then incubated with diester alkaloids. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to determinate the concentration of diester alkaloids to calculate the clearance rate. The cocktail method was used to evaluate the effects of oral administration of P. ginseng extracts on the activities of cytochrome P450 (CYP) isoforms in rats through the changes in the pharmacokinetic parameters of the probe drugs. The protein and gene expression of CYP3A2 and pregnane X receptor (PXR) in rats were evaluated by western blotting and quantitative PCR. The specific enzyme inhibitor method and human recombinant enzyme method were used to identify the involvement of sub-CYPs in the metabolism of diester alkaloids in human liver microsomes (HLMs). The clearances of aconitine, mesaconitine, and hypaconitine in the P. ginseng groups were lower than those of the control group. The areas under the curve of midazolam were 2.37 ± 1.05, 4.96 ± 0.51, and 6.23 ± 1.30 mg·L −1·h for the low-, medium-, and high-dose P. ginseng groups, respectively, which were higher than that of the control (2.23 ± 0.64 mg·L −1·h). The clearances of midazolam for the medium- (1.87 ± 0.16 L·h −1·kg −1) and high-dose (1.60 ± 0.34 L·h −1·kg −1) P. ginseng groups were lower than that of the control group (4.66 ± 1.43 L·h −1·kg −1). After exposure to P. ginseng extracts, the gene and protein expression levels of CYP3A4 and PXR were decreased. The hepatic metabolism rates of aconitine, mesaconitine, and hypaconitine in HLMs were decreased to 60.37%, 21.67%, and 10.11%, respectively, when incubated with ketoconazole, a specific inhibitor for CYP3A. The kinetic plots indicated that the K M and V max values of CYP3A4 were 10.08 ± 3.26 μM and 0.12 ± 0.01nmol·mg protein −1·min −1 for aconitine, 131.3 ± 99.75 μM and 0.73 ± 0.44 nmol·mg protein −1·min −1 for mesaconitine, and 17.05 ± 9.70 μM and 0.16 ± 0.04 nmol·mg protein −1·min −1 for hypaconitine, respectively. The in vitro mean intrinsic clearance rates by CYP3A4 were 0.0119, 0.0056, and 0.0091 mL·nmol CYP −1·min −1 for aconitine, mesaconitine, and hypaconitine, respectively. Therefore we implied that P. ginseng inhibited the metabolism of diester alkaloids in vitro and decreased the CYP3A4 enzyme activity as well as the gene and protein expression of CYP3A4 and PXR in vivo. CYP3A4 had a larger effect on diester alkaloid metabolism than the other human CYP isoforms, CYP1A2, CYP2C9, and CYP2E1.

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          Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.

          J Raucy (2003)
          Human CYP3A4 metabolizes a majority of clinically important substrates at variable rates. Accounting for these unpredictable rates is the wide variation noted in expression of this enzyme that is due, in part, to xenobiotic exposure. We used primary cultures of human hepatocytes from 17 individuals to assess the inducibility of CYP3A4 mRNA by prototypical inducers, dietary flavonoids, and botanicals. Those agents producing the greatest mRNA accumulation were 10 microM RIF (699 +/- 307% of control levels) 100 microM phenytoin (707 +/- 188% of control), 1 mM phenobarbital (536 +/- 207% of control), and 100 microM omeprazole (404 +/- 8% of control). Various concentrations of RIF were found to exhibit a typical dose-response curve for CYP3A4 mRNA content. A reporter gene assay using the human pregnane X receptor (hPXR) and promoter regions of CYP3A4 transiently transfected into HepG2 cells, exhibited inductive properties by the aforementioned therapeutics that were similar to those observed in hepatocytes. Several flavonoids including quercetin, resveratrol, and curcumin were also examined for their ability to induce CYP3A4 in human hepatocytes. Only quercetin produced accumulation of CYP3A4 mRNA (230 +/- 73% of control). When examined in a reporter gene assay, this flavonoid exhibited negligible increases in luciferase activity suggesting that quercetin induced CYP3A4 by mechanisms that may not involve PXR. We also examined the effects of herbals on CYP3A4 expression in human hepatocytes. Grapeseed extract, ginseng, silymarin, and kava-kava produced 270 +/- 73, 155 +/- 83, 100 +/- 10, and 386 +/- 185% of control CYP3A4 mRNA, respectively. Of these botanicals only kava-kava produced enhanced luciferase activity (11.6 +/- 2.1 fold above DMSO treated cells). Such results indicate that kava-kava required PXR to mediate CYP3A4 induction. Collectively, results demonstrated that several botancials induce CYP3A4, suggesting the potential for drug-herbal interactions.
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            Notoginsenoside R1 attenuates experimental inflammatory bowel disease via pregnane X receptor activation.

            Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling.
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              Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

              A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.
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                Author and article information

                Contributors
                Journal
                Evid Based Complement Alternat Med
                Evid Based Complement Alternat Med
                ECAM
                Evidence-based Complementary and Alternative Medicine : eCAM
                Hindawi
                1741-427X
                1741-4288
                2019
                21 March 2019
                21 March 2019
                : 2019
                : 3508658
                Affiliations
                1Beijing Institution of Radiation Medicine, Beijing 100850, China
                2Anhui Medical University, Hefei 230032, China
                3Beijing University of Technology, Beijing 100024, China
                Author notes

                Academic Editor: José L. Rios

                Author information
                http://orcid.org/0000-0001-9149-9107
                http://orcid.org/0000-0001-9298-872X
                http://orcid.org/0000-0003-4543-1974
                http://orcid.org/0000-0003-1131-5326
                Article
                10.1155/2019/3508658
                6463675
                29630fce-1a78-456d-929d-ec6148048b6e
                Copyright © 2019 Liang Yang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 January 2019
                : 22 February 2019
                : 5 March 2019
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81630131
                Award ID: 81673633
                Categories
                Research Article

                Complementary & Alternative medicine
                Complementary & Alternative medicine

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