JOURNAL OF ORGANIC CHEMISTRY
·
2021
·
IF 4.354
Jiawei Guo,Fengwei Li,Fangyuan Cheng,Li Ma,Xiaohui Liu,Pradeepraj Durairaj,Gang Zhang,Dandan Tang,Xiangtian Long,Wei Zhang,Lei Du,Xingwang Zhang,Shengying Li
Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enzyme involved in pikromycin biosynthesis from the bacterium Streptomyces venezuelae. Here, we identify the mutant PikCD50N as a potential biocatalyst, with a broad substrate scope, diversified product profile, and high catalytic efficiency, for preparation of HDMs. Remarkably, PikCD50N can mediate the drug-metabolizing reactions using the low-cost H2O2 as a direct electron and oxygen donor.
研究领域:
生物化学
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药理学
·
酶学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Yan-Ling Qian,Bang-Yin Tan,Shi-Shi Qin,Xian-Run Wu,Zhuo-Qi Shi,Yun-Li Zhao,Xiao-Dong Luo
Ethnopharmacological relevance Crotalari a assamica Benth, one of the folk medicinal plants in the "Dai" of China, is commonly used to treat liver and bile related diseases. However, its bioactive compounds and the mechanism related to traditional use remain unclear. Aim of the study To investigate the protective compounds and mechanism of C . assamica on drug-induced liver injury. Materials and methods The acetaminophen (APAP)-induced mice and cell model were carried out to reveal the liver protection of the extract of C . assamica (ECA) and bioactive compounds in vitro and in vivo . The protective pathway was explored using transcriptome analysis, and binding targets were predicted by structure-based binding prediction and dynamic simulation, which were further supported by qPCR and Western Blot experiments on the livers of treated mice. Results ECA reduced the contents of serum lactate dehydrogenase, aspartate transaminase, and alanine transaminase significantly, adjusted the oxidative indices of serum and liver tissues, and ameliorated inflammation and necrosis of liver tissues, as well as up-regulated expressions of NQO1, HO-1, Nrf2, p-AKT, BCL-2, AKT, and IL-6 in vivo . Moreover, its bioactive compound sarosiensin V increased the viability of APAP-induced HepG2 cells, and restored liver function activity, accompanied by enhanced antioxidation and mitochondrial membrane potential significantly. Conclusion C. assamica and its bioactive compound sarosiensin V inhibited oxidative stress, inflammation, apoptosis and necrosis of liver tissues, which was associated with the upregulation of the Nrf2 pathway, and then supporting its traditional use for liver protection.
研究领域:
药理学
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肝脏病学
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分子生物学
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天然产物化学
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氧化应激
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药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2022
·
IF 1.997
Li Zhang,Fugui Zhang,Yifei Xiao,Jianhao Du,Xingwang Zhang,Min Chen,Baojian Wu
CYP2E1 plays an important role in drug metabolism and drug-induced hepatotoxicity. Here, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in regulation of CYP2E1 expression and acetaminophen (APAP)-induced hepatotoxicity, and to determine the underlying mechanisms.Regulatory effects of REV-ERBα on CYP2E1 expression were assessed in vivo (using Rev-erbα-/- mice) and in vitro (using AML12 and HepG2 cells). In vitro microsomal CYP2E1 activity was probed using its specific substrate p-nitrophenol. Pharmacokinetic and acute toxicity studies were performed with Rev-erbα−/− and wild-type mice after APAP administration.We found that Rev-erbα ablation led to decreases in hepatic CYP2E1 expression and activity in mice. In line with this, APAP-induced hepatotoxicity was attenuated in Rev-erbα-deficient mice. The attenuated toxicity was due to down-regulation of APAP metabolism mediated by CYP2E1, which was evidenced by a decrease in formation of the toxic intermediate metabolite NAPQI (i.e. reduced APAP-cysteine and APAP-N-acetylcysteine levels). Furthermore, positive regulation of CYP2E1 expression by REV-ERBα was confirmed in both AML12 and HepG2 cells. Based on luciferase reporter assays, it was found that REV-ERBα regulated Cyp2e1 transcription and expression through repression of DEC2.In conclusion, REV-ERBα positively regulates CYP2E1 expression in mice, thereby affecting APAP metabolism and hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Infection and Drug Resistance
·
2023
·
IF 3.9
Huaqiao Tang,Nana Long,Lin Lin,Yao Liu,Jianlong Li,Fenghui Sun,Lijuan Guo,Fen Zhang,Min Dai
Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a very damaging and widespread pathogen, which is associated with many diseases and causes serious infections. MRSA infection can modulate the effects of drugs, which may occur through an influence on cytochrome P450 (CYP450), the drug-metabolizing enzyme in the liver. In this study, we evaluated the underlying mechanism of drug failure or poisoning in MRSA infection.Materials and methods: Mice were infected with three different doses of MRSA and the changes in CYP450 expression, cytokines, and oxidative stress markers were evaluated.Results: The administration of an attack dose of MRSA caused serious symptoms of infection and resulted in a 40% mortality rate in the mice. MRSA induced strong inflammation and oxidative stress in the mice, predominantly caused by significant increases in interleukin (IL)-1β, IL-4, IL-6, macrophage inflammatory protein, glutathione S-transferase (GST), and malondialdehyde, and decreases in oxygen radical absorbance capacity and glutathione levels in the liver. The expression of IL-2, tumor necrosis factor-α, and GST was briefly suppressed, but increased on days 3 and 7. The increased inflammation and oxidative stress further induced a significant decrease in the mRNA levels and activities of CYP450 1A2, 2D22, 2E1, and 3A1 in MRSA-infected mice within the first day of infection.Conclusion: These results show that MRSA infection leads to inflammation and oxidative stress, and reduces the expression levels and activities of drug metabolism enzymes, which decreased drug metabolism in patients infected with MRSA. Therefore, to avoid a drug overdose, the plasma concentration of patients with MRSA infection should be continuously monitored.
研究领域:
医学
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药理学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2014
·Vol. 42
·期 5
·839-843
·
IF 3.334
Ke Li,Sylvia Zhao,Lingling Zhang,Xiaoyun Wu,Pan Shu,Yang Wang,Hao Feng,Zheming Gu,Helen Han Hsu
It has been proposed that in humans 4β-hydroxycholesterol is formed mainly by CYP3A-catalyzed metabolism of cholesterol and thus may serve as an endogenous marker for CYP3A activity. The cynomolgus monkey is widely used as one of the nonrodent preclinical safety species in pharmaceutical research. In the current study, the potential application of 4β-hydroxycholesterol as an endogenous biomarker of CYP3A in response to drug treatment was evaluated in cynomolgus monkeys. Following multiple oral administration of rifampicin (a known CYP3A inducer) at 15 mg/kg/d in cynomolgus monkeys, the mean serum 4β-hydroxycholesterol levels increased 4-fold from the baseline of 55.3 ± 21.7 to 221 ± 53.4 ng/ml. The mean concentration ratios of 4β-hydroxycholesterol to cholesterol increased 5-fold. The data suggest that 4β-hydroxycholesterol formation from cholesterol metabolism was induced by rifampicin treatment in monkeys. This observation correlated with the metabolism of midazolam (a probe substrate of CYP3A activity) monitored in the same study. The serum exposure (area under the curve) of midazolam was markedly decreased by ∼95%, confirming the induction of CYP3A catalytic activity by rifampicin treatment in monkeys. The formation of 4β-hydroxycholesterol from cholesterol was specifically mediated by recombinant cynomolgus CYP3A8 and CYP3A5. The Km values of CYP3A8 and CYP3A5 for 4β-hydroxycholesterol formation from cholesterol were 204 and 104 μM, respectively, and Vmax values were 0.600 and 0.310 pg/pmol/min, respectively. The results suggest that 4β-hydroxycholesterol can be used as an endogenous biomarker to identify strong CYP3A inducers in cynomolgus monkeys, which may help to evaluate drug-drug interaction potential of drug candidates in preclinical settings.
研究领域:
药理学
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毒理学
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生物化学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
·
IF 4.374
Zhe Wang,Xiaoyu Wang,Zhen Wang,Yaqin Jia,Yuyi Feng,Lili Jiang,Yangliu Xia,Jun Cao,Yong Liu
Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a K i,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a K i,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [ I ] gut / K i,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.
研究领域:
药理学
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临床医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Haitao Liu,Tingting Tao,Zhongqiao Gan,Yingying Xie,Yaqing Wang,Yizhao Yang,Xu Zhang,Xianliang Li,Jianhua Qin
Cancer organoids have improved our understanding of recapitulating the histology, genotypes, and drug response of patient tumors for personalized medicine. However, the existing cancer organoids are typically grown in animal-derived matrices (e.g., Matrigel), which suffer from poor reproducibility and low throughput due to uncontrollable origin of seed cells, undefined matrix, and manual manipulation. Here, we report a new strategy to massively generate uniform pancreatic cancer organoids (PCOs) in a droplet system from single cells. This system is composed of all-in-water fluids that allow to mildly encapsulate single tumor cell into isolated droplet, which subsequently proliferate and self-assemble into organoids, resembling the initial state of a tumor in the body. This high-throughput method can produce thousands of organoids in a single batch. The droplets can serve as templates for synthesizing defined microgels with proper stiffness similar to that of native tumors, facilitating functional expressions of PCOs. These organoids exhibit superior uniformity and controllability in terms of size and morphologies compared with organoids cultured in manually dropped Matrigel, due mainly to the controllable number of initiating cells and defined microgels. In addition, the established organoids maintain the key biomarkers of pancreatic tumor (e.g., KRT7, KRT19 and SOX9) and higher expression of genes associated with drug metabolism confirmed by RNA-seq and PCR analysis. Furthermore, they show distinguishing responses to four clinically used drugs in a reproducible manner in automatic pipetting workstation, indicating the feasibility of the proposed method in high-throughput drug testing. The established strategy has integrated the formation, 3D cultures, and analysis of PCOs derived from single cells in a whole system, which may provide a novel platform for advancing organoids research with standardized procedure in translational applications.
研究领域:
肿瘤学
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再生医学
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生物工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2019
·
IF 2.983
Qingqing Yang,Jing Sun,Chuan Li,Haizhi Zhang,Weiren Xu,Changxiao Liu,Xuemin Zheng
Specific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α -hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC–MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC–MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by K m , V max and CL int . As a result, four CYP2D6 enzymes displayed diverse K m or V max towards MET and the values of CL int showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CL int *1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CL int *2/*1 = 74.87%) while CYP2D6*39 (CL int *39/*1 = 29.65%) and CYP2D6*10 (CL int *10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prominent influence of CYP2D6 polymorphisms on the metabolism of MET, which could offer valuable information for personalized administration of MET in clinic.
研究领域:
药理学
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临床医学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2014
·
IF 3.259
Junyan Wang,Minmin Huang,Haihong Hu,Lushan Yu,Su Zeng
The induction of drug-metabolising enzymes is being increasingly recognised for its clinical importance in drug research and development. In the present study, we used a pregnane X receptor (PXR)-mediated reporter gene assay to evaluate the activating effects of various food, herb, and horticultural plant constituents on the PXR and a UGT1A1 reporter gene DNA construct. The results showed that of 102 naturally occurring constituents tested, 50 activated the PXR signaling pathway and induced expression of the UGT1A1 -reporter gene DNA construct. Eleven constituents strongly induced gene expression (a response of >70% compared to that associated with rifampicin), and were further evaluated in in vitro experiments to confirm the induction of UGT1A1 mRNA and protein expression. The results suggest that foods and herbs containing these constituents should be consumed with caution to avoid undesirable drug–drug interactions with co-administered drugs that are substrates for UGT1A1.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2017
·
IF 5.246
Haijiao Zheng,Tenggao Zhu,Xiqian Li,Guan Wang,Qiong Jia
Biological-material-functionalized porous monoliths were prepared with lactoferrin and β-cyclodextrin via a click reaction. With the monolith as an extraction medium, a method combined with ICP-MS was developed for the determination of total gallium originating from metabolic residues of orally bioavailable gallium complexes with tris(8-quinolinolato)gallium (GaQ3) as a representative. The method exhibited favorable adsorption behaviors for gallium with high selectivity, low detection limit (2 ng L–1), and an enrichment factor of 29-fold with the sample throughput of 30 min–1. The developed approach was validated by the analysis of gallium from GaQ3 metabolic residues in a human cell line. Additionally, the practical applicability of this method was evaluated by the determination of gallium in human blood and urine samples from cancer patients. Results illustrated that the prepared monolith had potential in Ga-based anticancer drug analysis in complex biological samples.
研究领域:
分析化学
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生物医学工程
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL RESEARCH
·
2003
·Vol. 20
·期 9
·1401-1408
·
IF 2.354
Wanchana Suchada,Yamashita Fumiyoshi,Hashida Mitsuru
Purpose . To develop a quantitative structure/activity relationship (QSAR) model for predicting drug-CYP 3A4 interactions.
Method . The inhibitory effect of 53 structurally diverse drugs on the metabolism of 7-benzyloxy-4-trifluoromethyl coumarin (BFC) by recombinant CYP 3A4 was evaluated using a rapid microtiter plate assay. For each drug, a total of 220 two-dimensional topological indices were calculated using Molconn-Z software. Using a genetic algorithm-based partial least squares (GA-PLS) method, the desired descriptors were automatically selected to maximize the predictability of the IC 50 values.
Results . The IC 50 values of the drugs tested ranged from 9 nM to 2 mM. Based on the GA-PLS method, five principal components derived from 20 Molconn-Z descriptors were found to be effective for QSAR modeling. Interestingly, these descriptors suggested that the molecular size would be an important factor in determining drug-CYP 3A4 interactions. In the leave-one-out prediction, the r
pred and the standard error of prediction ( s ) were 0.754 and 0.787, respectively. Even in an external validation, the predictions were in good agreement with experimental values ( r
pred = 0.744, s = 0.769, n = 9).
Conclusions . The proposed model, in which two-dimensional topological descriptors were used as molecular descriptors, was able to predict drug-CYP 3A4 interactions with reasonable accuracy.
研究领域:
药理学
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计算生物学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2023
·
IF 4.1
Yehong Han,Mingyu Wang,Chunliu Yang,Zihui Zhao,Yanan Yuan,Hongyuan Yan
Osimertinib (OSIM) is widely used as a mainstream drug for the treatment of non-small cell lung cancer (NSCLC). However, the lack of a rapid extraction and detection method for OSIM and its metabolite, AZ-5104, has limited clinical drug metabolism and drug resistance research because the drug is unstable. In this study, a new ionic liquid hybrid hierarchical porous material (IL-HHPM) was synthesized with hierarchical porous structures, including micropores (1.6–2.0 nm), mesopores (2.0–50.0 nm), macropores (50.0–148.7 nm), and multiple functional groups via a one-step hydrothermal method using silanized ionic liquids (IL) as functionalized hybrid monomer. The IL-HHPM has the advantages of a high specific surface area (437.4 ± 4.6 m 2 g −1 ), sizable pore volume (0.74 cm 3 g −1 ), and fast mass transfer, additionally, the IL-HHPM adsorbed OSIM and AZ-5104 via π-π interactions and hydrogen bonding. OSIM and AZ-5104 were rapidly extracted and measured in human urine using rapid and miniaturized centrifugal spin-column extraction (MCSCE), which was based on the IL-HHPM. The optimized factors for the extraction recoveries of OSIM and AZ-5104 were adsorbent dosage (8.0 mg), sample volume (0.5 mL), and operation time (9.0 min), and markedly reduced the adsorbent dosage and operation time. The IL-HHPM-MCSCE-HPLC method displayed good linearity (0.02−5.00 μg mL −1 , r ≥ 0.9997), satisfying accuracy (spiked recoveries of 87.7%−100.0%), and good precision (RSDs ≤ 7.0%). The developed method is rapid, sensitive, and reproducible for the simultaneous determination of trace level of OSIM and AZ-5104 in human urine.
研究领域:
分析化学
·
药理学
·
临床医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）