Publications by authors named "Hui-Chang Bi"

51 Publications

PXR mediates mifepristone-induced hepatomegaly in mice.

Acta Pharmacol Sin 2021 Mar 29. Epub 2021 Mar 29.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing's syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr-knockout mice. The results demonstrated that high-dose Mif (100 mg · kg · d, i.p.) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg · d, i.p.) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg · d, i.p.) failed to induce hepatomegaly in Pxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
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http://dx.doi.org/10.1038/s41401-021-00633-4DOI Listing
March 2021

Schisandrol B promotes liver enlargement via activation of PXR and YAP pathways in mice.

Phytomedicine 2021 Apr 17;84:153520. Epub 2021 Feb 17.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address:

Background: Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera. It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration. It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown.

Purpose: This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly.

Methods: Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence.

Results: SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR, activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11, CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice.

Conclusion: These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.
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http://dx.doi.org/10.1016/j.phymed.2021.153520DOI Listing
April 2021

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ.

Front Pharmacol 2020 8;11:628314. Epub 2021 Feb 8.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
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http://dx.doi.org/10.3389/fphar.2020.628314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897654PMC
February 2021

Co-administration of Wuzhi tablet (Schisandra sphenanthera extract) alters tacrolimus pharmacokinetics in a dose- and time-dependent manner in rats.

J Ethnopharmacol 2020 Dec 5;263:113233. Epub 2020 Aug 5.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China. Electronic address:

Ethnopharmacology Relevance: Tacrolimus is a well-known potent but expensive immunosuppressant. We previously clarified the herb-drug interaction between tacrolimus and Wuzhi tablet (WZ), a prescribed drug of ethanol extract of Schisandra sphenanthera, and showed the ideal effect of WZ on maintaining therapeutic level of tacrolimus and reducing the total drug expense. However, WZ possesses a biphasic effect on regulating CYP3A (the major metabolizing enzyme of tacrolimus), which could induce the mRNA and protein expression after long-term treatment while transiently inhibit the activity of CYP3A. In clinic, clinicians are confused about the relationship between the blood concentration of tacrolimus and the dose and the duration of pretreatment of WZ. Therefore, the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus is urgently needed to be clarified to better combine the use of WZ and tacrolimus in clinic.

Aim Of The Study And Method: This study aimed to investigate the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus in rats.

Results And Conclusions: After pretreated rats with WZ for 0, 0.5, 2, 6, 12 or 24 h, the area under the curve (AUC) of tacrolimus was 2.27 ± 0.59, 1.87 ± 1.14, 2.86 ± 0.64, 1.62 ± 0.70, 1.54 ± 1.06 and 1.12 ± 0.69-fold of that of the tacrolimus alone group, respectively. The ratio of AUC of tacrolimus to that of the co-administration group with 0, 62.5, 125, 250, 500 or 750 mg/kg of WZ was 1.00: 1.07: 1.44: 2.60: 2.32: 2.42, respectively. These findings suggested that WZ increased tacrolimus AUC in a pretreatment time- and dose-dependent manner. In line with the in vivo findings, WZ extract inhibited CYP3A activity in a pre-treatment time- and concentration-dependent manner in human liver microsomes. In conclusion, the pharmacokinetics of tacrolimus was significantly affected by the pretreatment time and the dose of WZ. Oral pretreatment with WZ for 0-2 h or co-dosing of 250 mg/kg of WZ most significantly increased the blood concentration of tacrolimus. These findings would be helpful for guiding the reasonable use of WZ and tacrolimus in clinic.
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http://dx.doi.org/10.1016/j.jep.2020.113233DOI Listing
December 2020

Crotonpenoids A and B, Two Highly Modified Clerodane Diterpenoids with a Tricyclo[7.2.1.0]dodecane Core from : Isolation, Structural Elucidation, and Biomimetic Semisynthesis.

Org Lett 2020 06 26;22(11):4435-4439. Epub 2020 May 26.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, People's Republic of China.

Crotonpenoids A () and B (), two highly modified clerodane diterpenoids featuring a new 10-(butan-2-yl)-1,6,12-trimethyltricyclo[7.2.1.0]dodecane skeleton, were isolated from the leaves and twigs of . Their structures including the absolute configurations were determined by spectroscopic analysis, single-crystal X-ray diffraction, and biomimetic semisynthesis. Compounds and exhibited an agonistic effect on pregnane X receptor at 10 μM.
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http://dx.doi.org/10.1021/acs.orglett.0c01443DOI Listing
June 2020

Targeted bile acids and gut microbiome profiles reveal the hepato-protective effect of WZ tablet (Schisandra sphenanthera extract) against LCA-induced cholestasis.

Chin J Nat Med 2020 Mar;18(3):211-218

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510000, China. Electronic address:

Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) can significantly protect against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration. However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCA-induced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.
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http://dx.doi.org/10.1016/S1875-5364(20)30023-6DOI Listing
March 2020

AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation.

Oncogene 2020 01 17;39(3):637-650. Epub 2019 Sep 17.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.

Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction-oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.
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http://dx.doi.org/10.1038/s41388-019-1004-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962094PMC
January 2020

Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

Pharmacol Res Perspect 2017 06 17;5(3):e00305. Epub 2017 Apr 17.

Departments of Respiratory Medicine Pathology and Cancer Imaging British Columbia Cancer Agency, and the University of British Columbia Vancouver British Columbia Canada.

Although green tea ( sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.
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http://dx.doi.org/10.1002/prp2.305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464336PMC
June 2017

[Regulation of P-glycoprotein gene expression by PKC/NF-κB-PXR signaling pathway].

Yao Xue Xue Bao 2017 Jan;52(1):51-7

P-glycoprotein (P-gp), an ATP binding cassette protein, plays a major role in efflux transport of drugs and xenobiotics due to its abundant expression on several barriers. This study aimed to investigate the potential role of PKC/NF-κB-PXR signaling pathway in modulation of P-gp gene expression in human colon adenocarcinoma LS174T. The effect of PMA on MDR1 luciferase activity was investigated by PXR-MDR1 dual luciferase reporter gene assay. Real-time qPCR assay and Western blot analysis were used to study the gene expression of P-gp and NF-κB, respectively. Compared to the vehicle-treated group, PMA statistically decreased P-gp luciferase activity, mRNA expression and protein expression. Moreover, PMA treatment yielded a significant and dose-dependent increase in RelA/p65 translocation to nucleus. Meanwhile, a remarkable increase of the pho-IκBα status was observed in LS174T cells after treatment with PMA (1-100 nmol·L(-1)). In addition, knockdown of PKCα, NF-κB or PXR can significantly attenuate PMA-induced P-gp suppression. These results suggested that PKC/NF-κB-PXR signaling pathway might play crucial roles in modulation of P-gp gene expression.
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January 2017

[Determination of hepatic and small intestinal distribution of lignans of Wuzhi tablet in rats by liquid chromatography tandem mass spectrometry method].

Yao Xue Xue Bao 2016 12;51(12):1891-6

This study was aimed to determine the hepatic and small intestinal distribution of active lignans in rats after treated with Wuzhi tablet (WZ, Schisandra sphenanthera extract) by LC-MS/MS method. Male Sprague-Dawley rats were sacrificed at 0.25, 1.5, 4, 6, 10, 24 h after an oral administration of WZ, and then hepatic and small intestinal samples were collected for analysis. The results showed that concentrations of lignans in liver and small intestine of rats were decreased with WZ pretreated time. The concentrations of all lignans in rat liver and small intestine at 0.25 h were the highest after a single oral administration. All lignans was undetectable in all tissues 24 h after oral dosing, suggesting lignans of WZ were eliminated rapidly in rats. The concentrations of schisandrin A, schisandrol B and schisantherin A in small intestine were much higher than those in the liver, suggesting the effect of WZ on the intestinal metabolism enzyme might be more potent than that on the liver. In short, the current results suggest that lignans of WZ were not accumulated in rat liver and small intestine. The concentrations of lignans of WZ in small intestine were much higher than those in liver.
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December 2016

[Effect of long-term treatment of Wuzhi tablet on the expression and activity of cytochrome P450 3A in rats].

Yao Xue Xue Bao 2016 09;51(9):1407-11

The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tablet(WZ) on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3%(P < 0.05) and 48.2%(P < 0.05), respectively; and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9%(WZ pretreatment group) and 154.2%(WZ coadministered group) compared to that of control group. In conclusion, long-term treatment of WZ increased the m RNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.
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September 2016

[Construction and function identification of luciferase reporter gene vectors containing SNPs in NFKBIA gene 3'UTR].

Yao Xue Xue Bao 2016 Jan;51(1):80-5

This study aims to investigate the function of two SNPs (rs8904C > T and rs696G >A) in 3' untranslated region (3'UTR) of NFKBIA gene by constructing luciferase reporter gene. A patient's genomic DNA with rs8904 CC and rs696 GA genotype was used as the PCR template. Full-length 3'UTR of NFKBIA gene was amplified by different primers. After sequencing validation, these fragments were inserted to the luciferase reporter vector, pGL3-promoter to construct recombinant plasmids containing four kinds of haplotypes, pGL3-rs8904C/rs696G, pGL3-rs8904C/rs696A, pGL3-rs8904T/rs696G and pGL3-rs8904T/rs696A. Then these plasmids were transfected into LS174T cells and the luciferase activity was detected. Compared with pGL3-vector transfected cells (negative control), the luciferase activity of the four kinds of recombinant plasmids was significantly decreased (P < 0.001). For rs696G > A, the luciferase activity of the recombinant plasmids containing A allele (pGL3-rs8904C/rs696A and pGL3-rs8904T/rs696A) was about 45.1% (P < 0.05) and 56.1% (P < 0.001) lower than those containing G allele (pGL3-rs8904C/rs696G and pGL3-rs8904T/rs696G), respectively. For rs8904C > T, there were no significant differences in the luciferase activity between the recombinant plasmids containing T allele and those with C allele. Together, the luciferase reporter gene vectors containing SNPs in NFKBIA gene 3'UTR were constructed successfully and rs696G > A could decrease the luciferase activity while rs8904C >T didn't have much effect on the luciferase activity.
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January 2016

[Optimization of midazolam dosage and pharmacokinetics of CYP3A probe substrate in rats].

Yao Xue Xue Bao 2016 05;51(5):834-8

The study was conducted to evaluate the pharmacokinetics of midazolam (MDZ) under different oral dosages in rats, and determine the optimum oral dosage of MDZ, a CYP3 A probe substrate in vivo. Male Sprague-Dawley rats were given a single oral dosages of MDZ at 1,2,5,10,15 or 20 mg·kg(-1). Plasma concentrations of MDZ and its major metabolite 1-hydroxyl midazolam (1-OH MDZ) were determined at different time points using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental model. The C(max), AUC(0-t) and AUC0(∞) of MDZ and 1-OH MDZ were linearly increased over the dose range of 1-5 mg·kg(-1) (r > 0.99), but not at the dose of 15 or 20 mg·kg(-1). The AUC/Dose at 1-10 mg·kg(-1) were not significant different, but that of 15 or 20 mg·kg(-1) were significantly higher. No significant sedative reaction was observed in all the rats at dosages of 1-5 mg·kg(-1), however loss of righting reflex was observed in rats receiving dosages of 10-20 mg·kg(-1). In conclusion, the optimized oral dose of MDZ was 1-5 mg·kg(-1) when MDZ is used as the CYP3 A probe substrate in rats.
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May 2016

Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway.

Acta Pharmacol Sin 2016 Mar 25;37(3):382-9. Epub 2016 Jan 25.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Aim: The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect.

Methods: Male C57BL/6 mice were treated with SolB (200 mg · kg(-1) · d(-1), ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay.

Results: SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5-20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells.

Conclusion: SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.
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http://dx.doi.org/10.1038/aps.2015.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775844PMC
March 2016

Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress.

Cell Physiol Biochem 2015 28;35(2):710-21. Epub 2015 Jan 28.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

Background: Aberrant expression of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress.

Methods: Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress.

Results: NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking.

Conclusions: These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress.
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http://dx.doi.org/10.1159/000369731DOI Listing
October 2015

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain.

Acta Pharmacol Sin 2014 Dec 24;35(12):1577-85. Epub 2014 Nov 24.

College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China.

Aim: Para-aminosalicylic acid (PAS) is effective in the treatment of manganism-induced neurotoxicity (manganism). In this study we investigated the roles of P-glycoprotein (MDR1a) and multidrug resistance protein (MRP) in transporting PAS and its N-acetylated metabolite AcPAS through blood-brain barrier.

Methods: MDR1a-null or wild-type mice were intravenously injected with PAS (200 mg/kg). Thirty minutes after the injection, blood samples and brains were collected, and the concentrations of PAS and AcPAS in brain capillaries and parenchyma were measured using HPLC. Both MDCK-MDR1 and MDCK-MRP1 cells that overexpressed P-gp and MRP1, respectively, were used in two-chamber Transwell transport studies in vitro.

Results: After injection of PAS, the brain concentration of PAS was substantially higher in MDR1a-null mice than in wild-type mice, but the brain concentration of AcPAS had no significant difference between MDR1a-null mice and wild-type mice. Concomitant injection of PAS with the MRP-specific inhibitor MK-571 (50 mg/kg) further increased the brain concentration of PAS in MDR1a-null mice, and increased the brain concentration of AcPAS in both MDR1a-null mice and wild-type mice. Two-chamber Transwell studies with MDCK-MDR1 cells demonstrated that PAS was not only a substrate but also a competitive inhibitor of P-gp, while AcPAS was not a substrate of P-gp. Two-chamber Transwell studies with the MDCK-MRP1 cells showed that MRP1 had the ability to transport both PAS and AcPAS across the BBB.

Conclusion: P-gp plays a major role in the efflux of PAS from brain parenchyma into blood in mice, while MRP1 is involved in both PAS and AcPAS transport in the brain.
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http://dx.doi.org/10.1038/aps.2014.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261121PMC
December 2014

Erratum to "PXR-Mediated Upregulation of CYP3A Expression by Herb Compound Praeruptorin C from Peucedanum praeruptorum Dunn".

Evid Based Complement Alternat Med 2014 28;2014:721341. Epub 2014 Oct 28.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou 510006, China.

[This corrects the article DOI: 10.1155/2013/156574.].
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http://dx.doi.org/10.1155/2014/721341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220614PMC
March 2015

Inhibiton of cytochrome P450 isoenzymes and P-gp activity by multiple extracts of Huang-Lian-Jie-Du decoction.

J Ethnopharmacol 2014 Oct 8;156:175-81. Epub 2014 Sep 8.

School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuan Dong Road, Guangzhou University City, Guangzhou 510006, China. Electronic address:

Ethnopharmacological Relevance: Huang-Lian-Jie-Du-Decotion (HLJDD), an important traditional Chinese medicine formula, has been used for various diseases in clinical practice, and thus has high potential to induce cytochrome P450 (CYP) isoenzymes/P-glycoprotein (P-gp) mediated herb-drug interactions (HDIs) with other co-administered drugs. The purpose of this study was to investigate the in vitro effects of multiple extracts including aqueous extracts, total flavonoids, iridoids, alkaloids from HLJDD on the activities of CYPs in rats (CYP1A2, CYP2C6, CYP2D2, CYP2E1 and CYP3A1) and P-gp, and then to predict potential interactions with co-administered drugs.

Materials And Methods: The effects of the four extracts from HLJDD on the CYPs activity were evaluated in rat liver microsomes incubation system, and then determined by LC-MS/MS-based CYPs probe substrate assay. Caco-2 cell monolayer was used to investigate the effect of the four extracts on the efflux of Rhodamine 123 to evaluate their influences on P-gp activity.

Results: The results show that total flavonoids and alkaloids exibited strong inhibition on rat CYP isoenzymes activities. Total flavonoids exhibited different inhibitory effects on CYPs activities with an order of CYP3A1>CYP2C6>CYP2E1>CYP1A2>CYP2D2, and the values of IC₅₀ were 4.24, 8.16, 17.56, 19.03, 29.51 μg/mL, respectively. Total alkaloids possessed similar inhibition on CYPs and could strongly inhibit the activity of CYP2D2 (IC₅₀=2.38 μg/mL), CYP3A1 (IC₅₀=2.61 μg/mL), CYP2E1 (IC₅₀=22.35 μg/mL), CYP1A2 (IC₅₀=23.2 μg/mL) and CYP2C6 (IC₅₀=43.09 μg/mL). Moderate degree of inhibition on CYPs activities was observed in aqueous and total iridoids extracts. Results from transport assay revealed that total flavonoids and alkaloids exhibited significant inhibitory effect on P-gp activity as evidenced by strong inhibition on the efflux of Rhodamine-123 with IC₅₀ of 104.6 and 82.6 μg/mL. But aqueous extract showed weak and iridoids had negligible effect on P-gp activity.

Conclusions: This study clearly demonstrated that total flavonoids and alkaloids from HLJDD can significantly inhibit the activities of CYPs and P-gp, which should be taken into consideration to predict any potential HDIs when HLJDD and its bioactive components are co-administered with other therapeutic drugs metabolized by CYPs or transported by P-gp.
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http://dx.doi.org/10.1016/j.jep.2014.08.044DOI Listing
October 2014

N-methylnicotinamide and nicotinamide N-methyltransferase are associated with microRNA-1291-altered pancreatic carcinoma cell metabolome and suppressed tumorigenesis.

Carcinogenesis 2014 Oct 12;35(10):2264-72. Epub 2014 Aug 12.

Department of Pharmaceutical Sciences, SUNY-Buffalo, Buffalo, NY 14214, USA, Department of Biochemistry & Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA and

The cell metabolome comprises abundant information that may be predictive of cell functions in response to epigenetic or genetic changes at different stages of cell proliferation and metastasis. An unbiased ultra-performance liquid chromatography-mass spectrometry-based metabolomics study revealed a significantly altered metabolome for human pancreatic carcinoma PANC-1 cells with gain-of-function non-coding microRNA-1291 (miR-1291), which led to a lower migration and invasion capacity as well as suppressed tumorigenesis in a xenograft tumor mouse model. A number of metabolites, including N-methylnicotinamide, involved in nicotinamide metabolism, and l-carnitine, isobutyryl-carnitine and isovaleryl-carnitine, involved in fatty acid metabolism, were elevated in miR-1291-expressing PANC-1. Notably, N-methylnicotinamide was elevated to the greatest extent, and this was associated with a sharp increase in nicotinamide N-methyltransferase (NNMT) mRNA level in miR-1291-expressing PANC-1 cells. In addition, expression of NNMT mRNA was inversely correlated with pancreatic tumor size in the xenograft mouse model. These results indicate that miR-1291-altered PANC-1 cell function is associated with the increase in N-methylnicotinamide level and NNMT expression, and in turn NNMT may be indicative of the extent of pancreatic carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgu174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178474PMC
October 2014

Effect of Tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp.

Phytomedicine 2014 Apr 22;21(5):766-72. Epub 2014 Jan 22.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address:

We recently reported that Wuzhi tablet (WZ), a preparation of the ethanol extract of Wuweizi (Schisandra sphenanthera), had significant effects on blood concentrations of Tacrolimus (FK506) in renal transplant recipients and rats. The active lignans in WZ are schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, schisantherin A, and schisantherin B. Until now, whether the pharmacokinetics of these lignans in WZ would be affected by FK506 remained unknown. Therefore, this study aimed to investigate whether and how FK506 affected pharmacokinetics of lignans in WZ in rats and the potential roles of CYP3A and P-gp. After a single oral co-administration of FK506 and WZ, the blood concentration of lignans in WZ was decreased by FK506; furthermore, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was only 64.5%, 47.2%, 55.1% and 57.4% of that of WZ alone group, respectively. Transport study in Caco-2 cells showed that these lignans were not substrates of P-gp, suggesting decreased blood concentration of lignans by FK506 was not via P-gp pathway. Metabolism study in the human recombinant CYP 3A showed that these lignans had higher affinity to CYP3A than that of FK506, and thus had a stronger CYP3A-mediated metabolism. It was concluded that the blood concentrations of these lignans were decreased and their CYP3A-mediated metabolisms were increased in the presence of FK506 since these lignans had higher affinity to CYP3A.
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http://dx.doi.org/10.1016/j.phymed.2013.12.006DOI Listing
April 2014

PXR-Mediated Upregulation of CYP3A Expression by Herb Compound Praeruptorin C from Peucedanum praeruptorum Dunn.

Evid Based Complement Alternat Med 2013 26;2013:156574. Epub 2013 Nov 26.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou 510006, China.

We recently reported that Praeruptorin C effectively transactivated the mRNA, protein expression, and catalytic activity of CYP3A4 via the CAR-mediated pathway, but whether and how PC could affect the expression and catalytic activity of CYP3A4 via PXR pathway remains unknown. Therefore, in this study, the effect of PC on the CYP3A gene expression was investigated in mice primary hepatocytes after knockdown of PXR by transient transfection of PXR siRNA, and the gene expression, protein expression, and catalytic activity of CYP3A4 in the LS174T cells with PXR overexpression were determined by real-time PCR, western blot analysis, and LC-MS/MS-based CYP3A4 substrate assay, respectively. We found that the level of CYP3a11 gene expression in mouse primary hepatocytes was significantly increased by praeruptorin C, but such an induction was suppressed after knockdown of pregnane X receptor by its siRNA. In PXR-overexpressed LS174T cells, PC significantly enhanced CYP3A4 mRNA, protein expression, and functional activity through PXR-mediated pathway; conversely, no such increase was found in the untransfected cells. These findings suggest that PC can significantly upregulate CYP3A level via the PXR-mediated pathway, and this should be taken into consideration to predict any potential herb-drug interactions between PC, Qianhu, and the other coadministered drugs.
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http://dx.doi.org/10.1155/2013/156574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860132PMC
December 2013

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models.

Acta Pharmacol Sin 2014 Feb 23;35(2):283-91. Epub 2013 Dec 23.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Aim: To investigate the effects of phorbol 12-myristate 13-acetate (PMA), a PKC activator, on P-glycoprotein-mediated efflux of digoxin in two cell transport models.

Methods: Caco-2 cells, wild MDCKII cells (MDCKII-WT) and MDCKII cells transfected stably with human MDR1-gene encoding P-gp (MDCKII-MDR1) were examined. Cell viability was evaluated with MTT assay. Bidirectional transport of digoxin was evaluated in these cells. Intracellular ATP level was measured using ATP assay. P-gp ATPase activity was analyzed using a Pgp-Glo(TM) assay.

Results: PMA (10 μmol/L) did not reduce the viability of the 3 types of cells. In Caco-2 and MDCKII-MDR1 cell monolayers, PMA (1, 10 and 100 nmol/L) dose-dependently inhibited the basolateral to apical transport of digoxin, but did not change the apical to basolateral transport. In addition, PMA did not affect both the basolateral to apical and apical to basolateral transport of digoxin in MDCKII-WT cell monolayer. In agreement with the above results, PMA dose-dependently reduced intracellular ATP level and stimulated P-gp ATPase activity in both Caco-2 and MDCKII-MDR1 cells. Verapamil (a positive control, 100 μmol/L) caused similar inhibition on digoxin efflux as PMA did, whereas 4α-PMA (a negative control, 100 nmol/L) had no effect.

Conclusion: PMA significantly inhibited P-gp-mediated efflux of digoxin in both Caco-2 and MDCKII-MDR1 cell monolayers via PKC activation.
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http://dx.doi.org/10.1038/aps.2013.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651225PMC
February 2014

In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus.

Drug Metab Dispos 2014 Jan 6;42(1):193-9. Epub 2013 Nov 6.

School of Pharmaceutical Sciences (X.L.Q., X.P.X., Y.W., J.L.L, X.D.W., G.P.Z., M.H., H.C.B.) and The First Affiliated Hospital (X.C., C.X.W.), Sun Yat-sen University, Guangzhou, China; Department of Pharmacy, Pan Yu Central Hospital, Guangzhou, China (X.L.Q., H.Y.) and Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (Y.W., [the third author]).

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.
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http://dx.doi.org/10.1124/dmd.113.053892DOI Listing
January 2014

Regulation of human pregnane X receptor and its target gene cytochrome P450 3A by praeruptorin A isolated from the herbal medicine Peucedanum praeruptorum.

Planta Med 2013 Nov 13;79(16):1509-15. Epub 2013 Sep 13.

School of Pharmaceutical Sciences, Hainan Medical University, Haikou, China.

Qianhu, the dried roots of Peucedanum praeruptorum, is a well-known traditional Chinese medicinal herb which was officially listed in the Chinese Pharmacopoeia. Praeruptorin A is the major active constituent of Qianhu. Our previous studies show that praeruptorin effectively transactivated the protein expression and catalytic activity of cytochrome P450 3A4 via the constitutive androstane receptor-mediated pathway. However, the effect of praeruptorin on the transactivation of cytochrome P450 3A4 through pregnane X receptor pathway is still unclear. To further elucidate the role of the pregnane X receptor pathway in the up-regulation of cytochrome P450 3A4 by praeruptorin, in this study, the effect of praeruptorin on the cytochrome P450 3A4 gene expression was investigated in mouse primary hepatocytes after knockdown of the pregnane X receptor by transient transfection of its siRNA; and the gene expression, protein expression, and catalytic activity of cytochrome P450 3A4 in the LS174T cells with pregnane X receptor overexpression were determined by real-time PCR, Western blot analysis, and LC-MS/MS-based cytochrome P450 3A4 substrate assay, respectively. We found that the level of cytochrome P450 3a11 gene expression in mouse primary hepatocytes was significantly increased by praeruptorin, but such an induction was suppressed after knockdown of pregnane X receptor by its siRNA. Praeruptorin significantly induced cytochrome P450 3A4 mRNA, protein expression, and functional activity through pregnane X receptor-mediated pathway in pregnane X receptor-overexpression LS174T cells; conversely, induction was not found in LS174T cells untransfected with pregnane X receptor plasmids. These findings suggest that praeruptorin can significantly up-regulate cytochrome P450 3A4 gene via the pregnane X receptor-mediated pathway, and this should be taken into consideration in potential herb-drug interactions.
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http://dx.doi.org/10.1055/s-0033-1350795DOI Listing
November 2013

[Induction of UGT1A1 expression by praeruptorin A and praeruptorin C through hCAR pathway].

Yao Xue Xue Bao 2013 May;48(5):794-8

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

This study is purposed to investigate the effects of praeruptorin A (PA) and praeruptorin C (PC) on UGT1A1 in HepG2 cells through hCAR pathway. PA and PC were incubated with HepG2 cells for 24 h and 48 h, mRNA and protein expressions of UGT1A1 were determined by real-time PCR and Western blotting assays. Additionally, effects of PA and PC on UGT1A1 mRNA and protein expressions were also measured after transient transfection of a specific CAR siRNA for 72 h in HepG2 cells. UGT1A1 mRNA and protein expression levels were significantly increased by PA and PC after incubation for 48 h. Moreover, the mRNA and protein up-regulations of UGT1A1 were attenuated by transient transfection of a specific CAR siRNA, suggesting the induction was mediated by CAR. The results suggest that PA and PC can significantly up-regulate UGT1A1 expression partially via the CAR-mediated pathway.
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May 2013

Up-regulatation of CYP3A expression through pregnent X receptor by praeruptorin D isolated from Peucedanum praeruptorum Dunn.

J Ethnopharmacol 2013 Jul 20;148(2):596-602. Epub 2013 May 20.

School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuan Dong Road, University City, Guangzhou 510006, China.

Ethnopharmacological Relevance: Qianhu, the dried roots of Peucedanum praeruptorum DUNN (Umbelliferae), is a well-known traditional Chinese medicinal herb which was officially listed in the Chinese Pharmacopoeia. Praeruptorin D (PD) is one of the major active constituents of Peucedanum praeruptorum Dunn (Qianhu). The Pregnane X receptor (PXR) is an orphan nuclear receptor and plays a pivotal role in the activation of human cytochrome P450 3A4 (CYP3A4) gene.

Aim Of The Study: The purpose of this study was to investigate the effect of PD on the PXR-mediated transactivation of CYP3A4, and thus to predict potential herb-drug interactions between PD, Qianhu, and the other co-administered drugs that metabolized by CYP3A4.

Materials And Methods: The effect of PD on the Cyp3a11, mPXR mRNA expression in mice primary hepatocytes was measured using real-time PCR. The gene expression, protein expression, and catalytic activity of CYP3A4 in the LS174T cells after transfected with PXR expression plasmids were determined by real-time PCR, Western blot analysis, and LC-MS/MS based CYP3A4 substrate assay.

Results: The results revealed that the level of Cyp3a11 gene expression in mice primary hepatocytes was significantly increased by PD, but PD cannot induce the mPXR gene expression. On the other hand, CYP3A4 mRNA, protein expression and functional activity in PXR-over-expression LS174T cells were significantly increased by PD through PXR-mediated pathway; conversely, no significant change was found in the untransfected cells.

Conclusions: These findings suggest that PD can significantly up-regulate CYP3A4 expression and activity via the PXR-mediated pathway and this should be taken into consideration to predict any potential herb-drug interactions when PD and Peucedanum praeruptorum Dunn are co-administered with other drugs.
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http://dx.doi.org/10.1016/j.jep.2013.05.008DOI Listing
July 2013

Genetic polymorphisms of UGT1A8, UGT1A9, UGT2B7 and ABCC2 in Chinese renal transplant recipients and a comparison with other ethnic populations.

Pharmazie 2013 Apr;68(4):240-4

Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

Mycophenolate mofetil (MMF), a widely used immunosuppressant, is characterized by highly variable pharmacokinetics. UGT1A8, UGT1A9, UGT2B7 and ABCC2 have been proved to be critical genes associated with inter-individual variation of MMF pharmacokinetics. In this study, we investigated the genetic polymorphisms of UGT1A8*2, UGT1A8*3, UGT1A9 C-2152T, UGT1A9 T-275A, UGT1A9 T98C, UGT2B7*2, ABCC2 C-24T and ABCC2 C3972T in 200 Chinese renal transplant recipients and compared them with those in other ethnic groups reported in the literature, to start the exploration of a better use of MMF in Chinese. A much higher frequency of UGT1A8*2 variant allele was found in Chinese than in Caucasians and Africans, while the UGT2B7*2 variant allele was significantly rarer in Chinese than in Caucasians and Africans. For ABCC2, -24T allele was more common and 3972T allele was less common in Chinese than in Caucasians and Africans. However, none of the SNPs in UGT1A9 were present in our study population. The findings of this study suggest that Chinese renal transplant recipients may exhibit a response profile to MMF that is different from those of other ethnic groups.
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April 2013

Effect of long-term co-administration of Wuzhi tablet (Schisandra sphenanthera extract) and prednisone on the pharmacokinetics of tacrolimus.

Phytomedicine 2013 Feb 23;20(3-4):375-9. Epub 2012 Dec 23.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510060, China.

Tacrolimus (TAC) is an immunosuppressant that has been widely used alone or in combination with prednisone (PRED) to prevent acute rejection after organ transplantation. Wuzhi tablet (WZ, Schisandra sphenanthera extract) is often prescribed with TAC to prevent drug-induced hepatitis. We recently reported that WZ could significantly increase TAC blood exposure by inhibiting P-gp-mediated efflux and CYP3A-mediated metabolism of TAC. PRED is also a substrate of P-gp and is a weak inducer of CYP3A, and drug-drug interactions within this combination therapy might occur. Therefore, the purpose of this study was to investigate the effect of long-term treatment of WZ and PRED on the pharmacokinetics of TAC in rats. After 14 days of co-administration of WZ and PRED, the AUC(0-24h) of oral TAC was increased (from 59.6±37.3 to 95.3±39.4 ng h/ml, p=0.18) and the clearance was decreased (from 38.4±28.4 to 17.7±6.4 l/h/kg, p=0.15). When only co-administered with WZ, AUC(0-24h) of TAC was demonstrated a significantly increase (from 59.6±37.3 to 135.9±34.8 ng h/ml, p<0.05). The concomitant administration of PRED resulted in a reduction in the systemic exposure of TAC and an increase in its clearance, though neither was statistically significant. Thus, our study suggested that the presence of WZ and PRED still could increase the systemic exposure of TAC in rats. The drug-drug interactions among this combination therapy should still be taken into consideration in clinical practice.
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http://dx.doi.org/10.1016/j.phymed.2012.11.008DOI Listing
February 2013

Effect of Wuzhi tablet (Schisandra sphenanthera extract) on the pharmacokinetics of cyclosporin A in rats.

Phytother Res 2013 Aug 21;27(8):1255-9. Epub 2012 Sep 21.

Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

In our previous reports, Wuzhi tablet (an herbal preparation of ethanol extract of Wuweizi (Schisandra sphenanthera)) can significantly increase the blood concentration of tacrolimus and paclitaxel in rats by inhibiting the CYP3A-mediated metabolism and the P-gp-mediated efflux. Cyclosporin A (CsA), a well-known immunosuppressant agent, is also a substrate of CYP3A and P-gp. Therefore, this study aimed to investigate whether and how WZ affects pharmacokinetics of CsA in rats. The AUC0-48 h and Cmax of CsA were increased by 40.1% and 13.1%, respectively, with a single oral co-administration of WZ and high dose of CsA (37.8 mg/kg). Interestingly, after a single oral co-administration of WZ and low dose of CsA (1.89 mg/kg), the AUC0-36 h and Cmax of CsA were dramatically increased by 293.1% (from 1103.2 ± 293.0 to 4336.5 ± 1728.3 ng.h/mL; p < 0.05) and 84.1% (from 208.5 ± 67.9 to 383.1 ± 92.5 ng/mL; p < 0.05), respectively. The CL/F was decreased from 1.7 L/h/kg to 0.5 L/h/kg. Thus, the effect of WZ on high dose of CsA was not significant, but pharmacokinetic parameters of CsA at low dose were significantly influenced by co-administration of WZ. The herb-drug interaction should be taken into consideration at this situation.
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http://dx.doi.org/10.1002/ptr.4849DOI Listing
August 2013

The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.

Eur J Gastroenterol Hepatol 2012 Aug;24(8):958-64

Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, People's Republic of China.

Objective: To investigate the potential influence of 5-aminosalicylic acid (5-ASA) on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.

Methods: (a) The retrospective study included inflammatory bowel disease patients treated with azathioprine (AZA)/6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) levels were detected at stable medication points. (b) The prospective study was performed in active disease patients: 4 weeks of AZA 50 mg/day followed by concomitant 5-ASA 3 g/day for another 4 weeks. 6-TGN was analyzed at weeks 4 and 8.

Results: (a) Of the 139 retrospective study patients, 45 were on AZA/6-MP+5-ASA and 94 on AZA/6-MP alone. The myelotoxicity rates were 47 and 16%, respectively. Multivariates regression analysis indicated that the administration of concomitant 5-ASA was the only risk factor associated with myelotoxicity (odds ratio=3.45, 95% confidence interval 1.31-9.04, P=0.01). (b) Thiopurine methyltransferase activity was not significantly different between patients on AZA/6-MP+5-ASA and patients on AZA/6-MP alone (P=0.78). (c) 6-TGN levels were significantly higher in samples on AZA/6-MP+5-ASA than those on AZA/6-MP (P=0.003) alone. (d) Sixteen patients completed the prospective study. After 4 weeks on AZA 50 mg/day, 6-TGN levels of 13 patients were less than 230 pmol/8×10 RBC. After another 4 weeks' cotreatment with mesalazine 3 g/day, 12 patients had 6-TGN levels at least 230 pmol/8×10 RBC, five patients had 6-TGN levels at least 420 pmol/8×10 RBC, and two of these five patients developed myelotoxicity.

Conclusion: The risk of thiopurine-induced myelotoxicity markedly increases in patients treated with combined 5-ASA and 2 mg/kg/day AZA therapy, which may be correlated to the increase in 6-TGN. 50 mg daily AZA when concomitant 5-ASA might help maintain an effective 6-TGN level without increasing the risk of myelotoxicity.
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http://dx.doi.org/10.1097/MEG.0b013e3283545ae3DOI Listing
August 2012