Frontiers in Pharmacology
·
2018
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IF 3.831
Li Zhuo-Qing,Jiang Li-Long,Zhao Dong-Sheng,Zhou Jing,Wang Ling-Li,Wu Zi-Tian,Zheng Xian,Shi Zi-Qi,Li Ping,Li Hui-Jun
Dictamni Cortex (DC) has been reported to be associated with acute hepatitis in clinic and may lead to a selective sub-chronic hepatotoxicity in rats. Nevertheless, the potent toxic ingredient and the underlying mechanism remain unknown. Dictamnine (DTN), the main alkaloid from DC, possesses a furan ring which was suspected of being responsible for hepatotoxicity via metabolic activation primarily by CYP3A4. Herein, the present study aimed to evaluate the role of CYP3A4 in DTN-induced liver injury. The in vitro results showed that the EC50 values in primary human hepatocytes (PHH), L02, HepG2 and NIH3T3 cells were correlated with the CYP3A4 expression levels in corresponding cells. Furthermore, the toxicity was increased in CYP3A4-induced PHH by rifampicin, and CYP3A4 over-expressed (OE) HepG2 and L02 cells. Contrarily, the cytotoxicity was decreased in CYP3A4-inhibited PHH and CYP3A4 OE HepG2 and L02 cells inhibited by ketoconazole (KTZ). In addition, the hepatotoxicity of DTN in enzyme induction/inhibition mice was further investigated in the aspects of biochemistry, histopathology, and pharmacokinetics. Administration of DTN in combination with KTZ resulted in attenuated liver injury, including lower alanine transaminase and aspartate transaminase activities and greater AUC and Cmax of serum DTN, whereas, pretreatment with dexamethasone aggravated the injury. Collectively, our findings illustrated that DTN-induced hepatotoxicity correlated well with the expression of CYP3A4, namely inhibition of CYP3A4 alleviated the toxicity both in vitro and in vivo, and induction aggravated the toxicity effects.
研究领域:
药理学
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毒理学
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药学
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PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2020
·Vol. 128
·期 5
·661-668
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IF 2.651
Hongfang Li,Yunyan Tang,Weipeng Wei,Chengchen Yin,Fushan Tang
Saikosaponin-d (SSd) is a major bioactive triterpenoid saponin extracted from Bupleurum , which has anti-inflammatory, anticancer, antioxidative and anti-hepatic fibrosis effects. Due to the effects of Bupleurum -related formulations on cytochrome P450 (CYPs) expression still remain unclear, the combination therapies involved formulations containing Bupleurum may sometimes lead to unexpected drug-drug interactions in clinical practice. These interactions can limit the clinical applications of related formulations. In this study, we tried to explore the effects of SSd on CYP3A4 mRNA, protein expression and the enzyme activity in HepaRG cells by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blot (WB) and HPLC method, respectively. The interaction between SSd and CYP3A4 was analysed by molecular docking. HepaRG cells were cultured with different concentrations of SSd (0.5, 1, 5 and 10 μmol/L) for 72 hours. It is revealed that SSd can inhibit CYP3A4 mRNA and its protein expression, and also the enzyme activity. Molecular docking study demonstrated that SSd can bind to several key active sites of amino acid residues of CYP3A4 protein with hydrogen bonds and hydrophobic interactions. Thus, drug-drug interactions resulted by SSd inhibiting CYP3A4 need attention when formulations containing SSd or Bupleurum are co-administrated with drugs metabolized by CYP3A4.
研究领域:
药理学
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分子生物学
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细胞生物学
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药物代谢
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2024
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IF 4.5
Dong Wu,Yamei Lin
Up to now, the biocatalytic activity of nanozymes has been extensively studied, while little research focus on their inhibitory behaviors. Here, Co-based carbon material (Co-DMOF) containing abundant carboxylic acid groups was prepared, with defects introduced by COx escape during pyrolysis to achieve controllable activity. As a result, Co-DMOF exhibited biocatalytic activity similar to cytochrome P450 3A4 (CYP3A4) in the metabolism of 1,4-Dihydropyridine (1,4-DHP, a calcium channel blocker). Excitingly, studies on IC 50 and drug-drug interaction (DDI) suggested that Co-DMOF had similar inhibitory behaviors to CYP3A4. Moreover, Co-DMOF displayed excellent stability even under high temperature (100 °C), organic solvents, and a wide range of pH (4–9). Additionally, it can be reused for at least 7 times with only slight loss of activity. Therefore, Co-DMOF has great potential to become a low-cost alternative to CYP3A4 for drug dosage guideline, drug metabolism and DDI. This work provides more possibilities for expanding the CYP3A4-like nanozyme library.
研究领域:
生物化学
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药理学
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纳米医学
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
·
IF 4.3
Kaixuan Li,Guode Zhao,Lan Yang,Xingyu Gao,Yudi Jia,Yang Wang,Xiaohong Zhang,Weiwei Li,Ying Peng,Jiang Zheng
4-Methylquinoline (4-MQ) is a quinoline derivative widely present in groundwater and soil and has been reported to be genotoxic. The mechanisms of the toxic action remain unknown. This study aimed to elucidate the metabolic activation of 4-MQ and to determine the possible role of reactive metabolites in 4-MQ-induced liver injury in rats. In the present study, a hydroxylation metabolite (M1), a GSH conjugate (M2) and an NAC conjugate (M3) derived from 4-MQ were detected in vitro and in vivo . The structures of the two conjugates were verified by chemical synthesis, mass spectrometry, and nuclear magnetic resonance. CYP3A4 was found to dominate the hydroxylation of 4-MQ. Sulfotransferases also participated in the metabolic activation of 4-MQ. Pretreatment of primary hepatocytes with ketoconazole (KTC) or 2,6-dichloro-4-nitrophenol (DCNP) not only reduced the production of GSH conjugate M2 but also decreased the susceptibility of hepatocytes to the cytotoxicity of 4-MQ. Urinary NAC conjugate M3 was found in rats given 4-MQ, and M3 may be a potential biomarker for 4-MQ exposure.
研究领域:
毒理学
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药理学
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环境科学
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PubMed
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Expert Opinion on Drug Metabolism & Toxicology
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2023
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IF 4.3
Pin Jiang,Tao Chen,Lin-Feng Chu,Ren-Peng Xu,Jin-Ting Gao,Li Wang,Qiang Liu,Lily Tang,Hong Wan,Ming Li,Hong-Can Ren
Background Enhancing the precision of drug–drug interaction (DDI) prediction is essential for improving drug safety and efficacy. The aim is to identify the most effective fraction metabolized by CY3A4 (fm) for improving DDI prediction using physiologically based pharmacokinetic (PBPK) models.Research Design and Methods The fm values were determined for 33 approved drugs using a human liver microsome for in vitro measurements and the ADMET Predictor software for in silico predictions. Subsequently, these fm values were integrated into PBPK models using the GastroPlus platform. The PBPK models, combined with a ketoconazole model, were utilized to predict AUCR (AUCcombo with ketoconazole/AUCdosing alone), and the accuracy of these predictions was evaluated by comparison with observed AUCR.Results The integration of in vitro fm method demonstrates superior performance compared to the in silico fm method and fm of 100% method. Under the Guest-limits criteria, the integration of in vitro fm achieves an accuracy of 76%, while the in silico fm and fm of 100% methods achieve accuracies of 67% and 58%, respectively.Conclusions Our study highlights the importance of in vitro fm data to improve the accuracy of predicting DDIs and demonstrates the promising potential of in silico fm in predicting DDIs.
研究领域:
药理学
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药物代谢
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药学
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生物医学工程
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2019
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IF 3.414
Bin Xie,Yuan-Yuan Lu,Zhuo-Hui Luo,Zhao Qu,Chun-Ge Zheng,Xin-An Huang,Hong-Yan Zhou,Ying-Jie Hu,Xiao-Ling Shen
Ethnopharmacological relevance Marsdenia tenacissima (Roxb.) Wight et Arn is a vine distributed in southwest area of China and used in folk medicine for treatment of tumors. Recent decades of studies on this plant reveal its synergistic effects with certain anticancer drugs in cancer therapy. In our previous study, an extract ETA which contains total aglycones made from M. tenacissima significantly enhanced antitumor activity of paclitaxel in tumor-bearing mice. However, the effective constituents in ETA and the underlying mechanisms remain unclear. Aim of the study Reveal the active components in ETA as well as the molecular mechanism in enhancing antitumor efficacy of paclitaxel. Material and methods Main constituents in ETA were purified by chemical methods. Effects of the purified constituents on metabolic activity of CYP450 enzymes were evaluated in human liver microsomes. Ability of the constituents to enhance antitumor activity of paclitaxel were investigated in nude mice bearing HeLa tumors. Pharmacokinetic study was performed in SD rats . Molecular docking was carried out for investigation of drug-protein interactions. Results Three main C 21 steroidal aglycones, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B ( MT1 ), 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B ( MT2 ) and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B ( MT3 ), together with tenacigenin B ( MT4 ) was prepared from ETA. Among them, MT1 , MT2 and MT3 strongly inhibit the metabolic activity of CYP3A4 . MT2 also showed inhibitory effects on CYP2C8 , CYP2B6 and CYP2C19 . In HeLa tumor xenografts, MT1 , MT2 and MT3 (30 mg/kg) did not affect tumor growth themselves, but significantly enhanced paclitaxel-induced growth inhibition. In addition, coadministration of MT2 with paclitaxel resulted in significant reduction of liver CYP2C8. In pharmacokinetic study, MT2 significantly increased the blood concentration of paclitaxel with increased AUC value by 2.2–5.3 folds. Molecular docking analysis suggested hydrophobic interaction modes of tenacigenin B derivatives with CYP3A4, and also the essential roles of the C-11 and C-12 ester groups for effective interaction with CYP3A4. Conclusion Our study proves that, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B, 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B, which are the main constituents of ETA, are active inhibitors of CYP3A4 with potential to increase therapeutic efficacy of anticancer drugs that are substrates of CYP3A4. Tenacigenin B derivatives with C-11 and C-12 ester group substitutions, or at least a large part of them, are active components in ETA and M. tenacissima to enhance in vivo antitumor efficacies of paclitaxel.
研究领域:
药理学
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肿瘤学
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民族药理学
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生物化学
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分子生物学
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PubMed
高影响因子
BIOMACROMOLECULES
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2024
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IF 5.5
Yuhan Yang,Yangyi Chen,Yue Wei,Wei Wu,Qing Wang,Tianyun Xue,Xiaoyan Zhang,Wei Chen,Wei Zhang
A drug delivery system based on silybin-conjugated chitosan (CS-SB) polymeric micelles was developed to improve the oral absorption of doxorubicin (DOX). SB was grafted to CS via succinic acid, and CS-SB was identified by 1H NMR and FT-IR. The DOX-loaded micelles were prepared by self-assembly, and the characteristics of micelles, including a small particle size of 167.8 ± 2.3 nm, a high drug loading capacity of 8.59%, and a low critical micelle concentration of 1.3 × 10–5 g/mL, were demonstrated. The micelles showed oral bioavailability of up to 193% versus DOX·HCl. The cytotoxicity test showed the biosafety of CS-SB and the potential of reductive DOX-induced cardiotoxicity. The inhibition of P-gp efflux and CYP3A4 enzyme in CS-SB micelles was confirmed by cellular uptake and enzyme activity inhibition tests. The endocytosis process of micelles was revealed by an endocytosis inhibition test. The findings exhibited the potential of CS-SB micelles in drug delivery.
研究领域:
药剂学
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药理学
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纳米技术
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药物递送
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生物医学工程
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Xu Wang,Lingwen Dong,Guode Zhao,Weiwei Li,Ying Peng,Jiang Zheng
2,3,5,4′-Tetrahydroxy stilbene-2-Ο- β -D-glucoside (TSG) and emodin (EMD) are two main components of Polygonum multiflorum Thunb. (PMT). Its root is widely used as herbal medicine and supplement. However, PMT-induced liver injury has drawn increasing attention. The purpose of this study was to investigate the interaction of TSG with EMD in the aspects of enzymology , pharmacokinetics , and hepatotoxicity. Co-administration with TSG increased internal exposure of EMD, EMD-derived hepatic protein adduction, and EMD-induced liver injury in mice. Mouse and human liver microsomal incubation study demonstrated that co-incubation with TSG decreased the formation of hydroxylation metabolites of EMD. Human recombinant cytochrome P450 enzyme incubation study showed that TSG induced time-, concentration-, NADPH-dependent and irreversible inhibition of CYP2C19 and CYP3A4 . An epoxide metabolite derived from TSG was responsible for the observed enzyme inactivations. The findings allow us to better understand the mechanisms by which herbal processing detoxifies raw PMT.
研究领域:
药理学
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毒理学
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酶学
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中药学
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PubMed
高影响因子
Frontiers in Pharmacology
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2025
·
IF 4.8
Yuxin Shen,Fengsheng Hong,Hualu Wu,Xiaohai Chen,Hailun Xia,Ren-ai Xu,Guanyang Lin,Lu Shi
This study aimed to examine the potential drug-drug interaction (DDI) between vandetanib and luteolin in vivo and in vitro, with the objective of establishing a scientific foundation for their appropriate utilization in clinical settings. Sprague-Dawley (SD) rats were randomly divided into two groups: a control group (vandetanib administered by gavage alone) and an experimental group (vandetanib and luteolin administered together). A series of blood samples were collected at different time intervals. The plasma concentrations of vandetanib and its metabolite N-demethyl vandetanib in rats were determined using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Incubation systems were set up with rat liver microsomes (RLM) and human liver microsomes (HLM) to measure the Michaelis-Menten constant (Km) and half-maximum inhibitory concentration (IC50) values. Additionally, the inhibitory mechanism of luteolin on vandetanib was also investigated. Ultimately, the molecular mechanism of inhibition was examined through the utilization of molecular docking techniques. In vivo animal experiment results showed that compared with the control group, the AUC(0-t) and Cmax of vandetanib in the experimental group were significantly increased. The findings from the in vitro experiments revealed that luteolin exhibited a moderate inhibitory effect on the metabolism of vandetanib. The IC50 values for RLM and HLM were determined to be 8.56 μM and 15.84 μM, respectively. The identified inhibition mechanism was classified as mixed. This study utilized molecular docking analysis to provide additional evidence supporting the competitive inhibition of luteolin on vandetanib in CYP3A4. The data presented in our study indicated a potential interaction between vandetanib and luteolin, which may necessitate the need for dose adjustment during their co-administration in clinical settings.
研究领域:
药理学
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临床医学
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分子生物学
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PubMed
高影响因子
Arabian Journal of Chemistry
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2024
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IF 5.3
Xiaohai Chen,Fengsheng Hong,Hualu Wu,Yuxin Shen,Hailun Xia,Ren-ai Xu,Lu Shi
The primary objective of this study was to investigate the effects of baicalein and fangchinoline on the metabolism of abemaciclib. We hypothesized that these two natural compounds could significantly affect the metabolism of abemaciclib by inhibiting the activity of the CYP3A4 enzyme, thus potentially increasing its concentration in the body. In vitro , rat liver microsomes (RLM) and human liver microsomes (HLM) were employed to explore the inhibitory effects and mechanisms of baicalein and fangchinoline on abemaciclib. In vivo , twelve healthy male Sprague-Dawley (SD) rats were randomly assigned to three groups: Group A (control group), Group B (baicalein), and Group C (fangchinoline). The concentrations of abemaciclib and its metabolite N-desethylabemaciclib (M2) were evaluated using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Finally, molecular docking method was employed to understand the interaction between abemaciclib and baicalein. It was indicated by the in vitro findings that both baicalein and fangchinoline inhibited abemaciclib metabolism in RLM through a mixed mechanism of competitive and non-competitive inhibition pathway. In HLM, baicalein inhibited abemaciclib metabolism by employing a hybrid mechanism of uncompetitive and non-competitive inhibition, while fangchinoline exhibited its inhibition in a competitive manner. In vivo , pharmacokinetic experiments revealed significant increases for AUC (0-t) and AUC (0-∞) of abemaciclib in Group B and Group C when compared to Group A, while the plasma clearance (CLz/F) of abemaciclib exhibited significant reductions. Moreover, molecular docking studies showed that both abemaciclib and baicalein docked to the active pocket of CYP3A4. This study demonstrated that the co-administration of baicalein or fangchinoline significantly affected the metabolism of abemaciclib, providing valuable insights for its clinical application.
研究领域:
药理学
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分子生物学
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临床医学
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高影响因子
ARCHIVES OF PHARMACAL RESEARCH
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2014
·Vol. 37
·期 12
·1617-1623
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IF 1.751
Shi Lei,Dang Xue-Liang,Liu Xin-You,Wei Hua-Mei,Yang Meng-Meng,Zhang Yan
Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A4 which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE). CBZE is an active and toxicity metabolite, and it is a substrate of MRP-2. Using CBZ for a long time can cause hepatic injury. Sophora flavescens (SF) is a medicinal herb used for the protected hepatic injury. This study investigated the acute and chronic effects of SF on the pharmacokinetics of CBZ in rats. The concentrations of CBZ and CBZE in plasma and tissues were determined by HPLC method. The results showed that SF which significantly decreased the AUC 0-t of CBZ, increased CBZE conversely. Tissue analysis showed that the concentrations of CBZ and CBZE in brain and liver were decreased by SF. In addition, the distribution of CBZE in kidney was reduced significantly, which influenced the CBZE excretion and increased the drug toxic potentially. Results in the current study suggest that patients using CBZ might be cautioned in the use of SF extract or Sophora -derived products. Meanwhile, patients receiving drugs which are substrates of CYP 3A4 and/or MRP-2 should be advised of the potential herb–drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.
研究领域:
药理学
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中药学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 5.6
Jinyu Hu,Haoxin Fu,Ruibin Li,Peiqi Wang,Jun Wu,Lu Cao,Chenjian Zhou,Ren-ai Xu
Fexinidazole is a ctirical treatment for Human African trypanosomiasis in Africa, but its metabolic characteristics are not fully understood. This study investigated the impacts of CYP3A4 genetic polymorphisms and (−)-epigallocatechin gallate (EGCG) on the metabolism of fexinidazole in vitro (rat liver microsomes (RLM), human liver mircosomes (HLM), and nine CYP3A4 variants) and in vivo (rat) models. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was utilized to quantify fexinidazole and its metabolites. The results showed that fexinidazole was metabolized mainly by CYP3A4, which was significantly modulated by CYP3A4 polymorphisms. In addition, EGCG significantly inhibited the metabolism of fexinidazole in both RLM (IC 50 = 8.02 ± 0.28 μM) and HLM (IC 50 = 9.97 ± 0.43 μM) via mixed-type inhibition mechanisms. In vivo , co-administration of EGCG significantly altered the pharmacokinetic parameters of fexinidazole, increasing the AUC and C max by approximately 1.46 and 1.44-fold, respectively, while decreasing clearance (CL z/F ). Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time.
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