INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Lihui Qiu,Qian Li,Jiangeng Huang,Qi Wu,Kun Tu,Ya Wu,Xin Zhang,Junyi Qian,Ran Zhang,Gao Li,Minghui Sun,Luqin Si
The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG 2k -PCL x polymeric micelles (mPEG 2k -PCL 2k , mPEG 2k -PCL 3.5k , mPEG 2k -PCL 5k and mPEG 2k -PCL 10k ) ranging from 20 to 100 nm were prepared to investigate the inhibitory or inductive activities by in vitro incubations of rat liver microsomes and primary rat hepatocytes. Inhibition of these polymeric micelles on CYP1A2 , CYP2B1 , CYP2C6, CYP2C11 , CYP2D2 and CYP3A1/2 isoenzymes were observed above their critical micelle concentrations (>10 μg·mL −1 ) and in a concentration-dependent manner. The mPEG 2k -PCL 2k micelles showed the strongest inhibition of CYP1A2, followed by CYP2C11. The micelles with lower molecular weight PCL segment exhibited more potent inhibitory potential. Induction on CYP1A2, CYP2B1 and CYP3A1/2 activity (2.1–7.2-fold, 1.5–2.4-fold and 1.3–3.0-fold, respectively) were detected at all tested concentrations (0.1–1000 μg·mL −1 or 0.1–100 μg·mL −1 ). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG 2k -PCL x micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG 2k -PCL x micelles can interfere with the normal metabolic function of CYP450s in vitro , indicating polymeric micelles as promising drug nano-carriers might cause micelle–drug interaction and the in vivo interaction deserves further investigation.
研究领域:
药理学
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毒理学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2012
·Vol. 13
·期 12
·17006-17018
·
IF 2.598
Beihua Bao,Ting Geng,Yudan Cao,Weifeng Yao,Li Zhang,Anwei Ding
The aim of this study was to find out whether Schizonepetin influences the pharmacokinetics of the main substrates drugs of CYP1A2, CYP3A1/2, CYP2E1, CYP2C19 and CYP2D6 in rats; the influence on the levels of CYP mRNA was also studied. Phenacetin, dapsone, chlorzoxazone, omeprazole and metoprolol were selected as probe substrates for CYP1A2, CYP3A1/2, CYP2E1, CYP2C19 and CYP2D6 respectively. HPLC methods were employed for the determination of these substrates in plasma and the pharmacokinetic parameters were calculated. Real-time RT-PCR was used to determine the effects of Schizonepetin on the mRNA expression of CYP3A1, CYP1A2 and CYP2E1 in the rat liver. After the rats were orally administrated with Schizonepetin once a day for seven consecutive days, there were significant differences in plasma concentration of phenacetin, dapsone, chlorzoxazone and metoprolol, but not omeprazole, as compared with pre-administration. In addition, Schizonepetin induced the expression of CYP3A1, CYP1A and CYP2E1 at dosages of 24 and 48 mg/kg. Our results indicated that Schizonepetin had significant induction effects on CYP3A1/2 and inhibition effects on CYP1A2, CYP2E1 or CYP2D6 as oriented from the pharmacokinetic profiles of the substrates. Moreover, in the mRNA expression levels, Schizonepetin could induce the mRNA expression of CYP3A1, CYP1A and CYP2E1. In conclusion, co-administration of some CYP substrates with Schizonepetin may lead to an undesirable herb-drug interaction.Keywords:Schizonepetin;Cytochrome P450;substrates drugs;pharmacokinetic parameters;mRNA;real-time RT-PCR
研究领域:
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2021
·
IF 8.071
Xia Lv,Jing-Xin Li,Jia-Yue Wang,Xiang-Ge Tian,Lei Feng,Cheng-Peng Sun,Jing Ning,Chao Wang,Wen-Yu Zhao,Ya-Chen Li,Xiao-Chi Ma
Carbendazim (CBZ), a broad-spectrum pesticide frequently detected in fruits and vegetables, could trigger potential toxic risks to mammals. To facilitate the assessment of health risks, this study aimed to characterize the cytochrome P450 (CYPs)-mediated metabolism profiles of CBZ by a combined experimental and computational study. Our results demonstrated that CYPs-mediated region-selective hydroxylation was a major metabolism pathway for CBZ in liver microsomes from various species including rat, mouse, minipig, dog, rabbit, guinea pig, monkey, cow and human, and the metabolite was biosynthesized and well-characterized as 6-OH-CBZ. CYP1A displayed a predominant role in the region-selective hydroxylation of CBZ that could attenuate its toxicity through converting it into a less toxic metabolite. Meanwhile, five other common pesticides including chlorpyrifos-methyl, prochloraz, chlorfenapyr, chlorpyrifos , and chlorothalonil could significantly inhibit the region-selective hydroxylation of CBZ, and consequently remarkably increased CBZ exposure in vivo . Furthermore, computational study clarified the important contribution of the key amino acid residues Ser122, and Asp313 in CYP1A1, as well as Asp320 in CYP1A2 to the hydroxylation of CBZ through hydrogen bonds . These results would provide some useful information for the metabolic profiles of CBZ by mammalian CYPs, and shed new insights into CYP1A-mediated metabolic detoxification of CBZ and its health risk assessment.
研究领域:
药理学
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毒理学
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计算化学
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实验生物学
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产品关联
DOI
PubMed
高影响因子
ENZYME AND MICROBIAL TECHNOLOGY
·
2019
·
IF 3.553
Kui Wu,Ying Zhang,Qingdi Sun,Yuxin Chai,Qian He,Xiantai Zhou,Xiaohui He,Hongbing Ji
A novel hybrid material with flower-mimicking morphology was fabricated with a facile coprecipitation method, and cytochrome P450 enzyme and cobalt phosphate were employed as organic and inorganic components, respectively. The hybrid nano-flowers showed excellent catalytic performance in the oxidative coupling of benzylamine, including the high conversion (99.9%) and selectivity (97.9%) in mild reaction conditions, as well as the satisfactory stability in the recycling experiments. Compared to free enzyme, the as-obtained materials exhibited enhanced activity. Such results indicate that the hybrid materials are potentially good candidates in the industrial enzyme catalysis.
研究领域:
生物化学
·
材料科学
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酶工程
✓ 已验证
DOI
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2018
·Vol. 33
·期 4
·e4454
·
IF 1.688
Jing-Xian Zhang,Mei-Juan Qi,Mei-Zhi Shi,Jun-Jun Chen,Xiang-Qi Zhang,Jiao Yang,Ke-Zhi Zhang,Yong-Long Han,Cheng Guo
Danhong injection (DHI) is made from Salvia miltiorrhiza Bunge. and Carthamus tinctorius L. extract and is widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. This study aimed to evaluate the effect of DHI on cytochrome P450 (CYP450) enzymes in vitro to predict drug–drug interactions based on CYP450 as combination therapy. To assess the inhibitory effect of DHI on CYP450, we detected the IC 50 value of DHI on CYP450 in vitro by liquid chromatography/tandem mass spectrometry (LC–MS/MS). Simultaneously, the induction effect of DHI on CYP450s was also evaluated. The relative induction ratios of DHI on CYP1A2, CYP2B6 and CYP3A4 activity were calculated by LC–MS/MS. The expression level of CYP3A4 mRNA was determined by reverse transcription PCR (RT-PCR). The LC–MS/MS data showed DHI intensively inhibit CYP2A6 activity and the intensity of inhibition was followed by CYP2C8, CYP3A4, CYP2C19, CYP2B6, CYP2D6, CYP1A2, CYP2E1 and CYP2C9 in vitro . The results of RT-PCR showed that there is a certain induction of DHI on CYP3A4 mRNA in human primary hepatocytes in vitro . The study suggested that drug–drug interactions might occur in clinical co-administration of drugs owing to the CYP2A6 inhibition and CYP3A4 induction.
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
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-12
·
IF 5.228
Chen Ang,Zhou Xiaojing,Tang Shuowen,Liu Mingyao,Wang Xin
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a natural naphthoquinone compound isolated from roots of Plumbago zeylanica L., has drawn a lot of attention for its plenty of pharmacological properties including antidiabetes and anti-cancer. The aim of this study was to investigate the effects of plumbagin on CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver and evaluate the potential herb-drug interactions using the cocktail approach. All CYP substrates and their metabolites were analyzed using high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). Plumbagin presented non-time-dependent inhibition of CYP activities in both human and rat liver. In humans, plumbagin was not only a mixed inhibitor of CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, but also a non-competitive inhibitor of CYP1A2, with K i values no more than 2.16 μM. In rats, the mixed inhibition of CYP1A2 and CYP2D1, and competitive inhibition for CYP2B1, CYP2C11 and CYP2E1 with K i values less than 9.93 μM were observed. In general, the relatively low K i values of plumbagin in humans would have a high potential to cause the toxicity and drug interactions involving CYP enzymes.
研究领域:
药理学
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分析化学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yuqian Chi,Xiaoliang Zhu,Yaxuan Chen,Xin Li,Ziyi Jiang,Xiaoyang Jian,Mengyuan Lian,Xiaodi Wu,Lei Wang,Mengmeng Sun,Xiaowei Shi
Piperlonguminine (PLG) is a major alkaloid found in Piper longum fruits. It has been shown to possess a variety of biological activities, including anti-tumor, anti-hyperlipidemic, anti-renal fibrosis and anti-inflammatory properties. Previous studies have reported that PLG inhibits various CYP450 enzymes. The main objective of this study was to identify reactive metabolites of PLG in vitro and assess its ability to inhibit CYP450. In rat and human liver microsomal incubation systems exposed to PLG, two oxidized metabolites (M1 and M2) were detected. Additionally, in microsomes where N -acetylcysteine was used as a trapping agent, N -acetylcysteine conjugates (M3, M4, M5 and M6) of four isomeric O -quinone-derived reactive metabolites were found. The formation of metabolites was dependent on NADPH. Inhibition and recombinant CYP450 enzyme incubation experiments showed that CYP3A4 was the primary enzyme responsible for the metabolic activation of PLG. This study characterized the O -dealkylated metabolite (M1) through chemical synthesis. The IC 50 shift assay showed time-dependent inhibition of CYP3A4, 2C9, 2E1, 2C8 and 2D6 by PLG. This research contributes to the understanding of PLG-induced enzyme inhibition and bioactivation.
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
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2016
·
IF 3.13
Qian Zhao,Feng Shi,Lin Zhu
Humic acid (HA) is a major component of dissolved organic matter , is ubiquitous in the aquatic environment and influences the biological toxicity of organic pollutants. In this study, we investigated the cytochrome P450 1A (CYP 1A) mRNA expression and ethoxyresorufin- O -deethylase (EROD) activity in the gills and liver of zebrafish following exposure to the s -triazine herbicide prometryn with or without HA present. Prometryn induced both CYP 1A mRNA expression and EROD activity. The CYP 1A mRNA expression of zebrafish that were exposed to a combination of prometryn and HA was increased compared to those exposed to prometryn alone. A likely cause for CYP 1A induction is the impact of special components of HA, functioning as aryl hydrocarbon receptor (AHR) agonists. In combination with HA, these increase prometryn levels in tissues. Similar results for EROD activity were evident. In our time course study, CYP 1A mRNA expression reached maximum values during 24 h. This revealed CYP 1A mRNA transcription as a comparatively sensitive toxicity index. In a recovery experiment, we found a faster decrease of CYP 1A mRNA expression to control levels (CK) in gills compared to liver tissue. Following exposure to HA, CYP 1A mRNA expression in liver tissue displayed a faster decrease to CK levels. HA induced enhanced metabolic rates for prometryn. In contrast, recovery regularity of CYP 1A expression in gills was independent of the presence of HA. This result indicates different detoxification mechanisms for HA in liver and gills.
研究领域:
环境毒理学
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水生生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2022
·Vol. 23
·期 13
·1054-1066
·
IF 3.408
Chai Yuan-Yuan,Xu Yun-Xia,Xia Zi-Yin,Li An-Qin,Huang Xin,Zhang Lu-Yong,Jiang Zhen-Zhou
Background: The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have been reported. Since Cytochrome P450 (CYP) enzymes play an important role in drug interactions. The evaluation
of the influence of herbal medicines on the activities of CYPs is beneficial to promote scientific and rational clinical use of herbal medicines. Objective: Herein, we aimed to develop and validate a method to simultaneously quantify seven CYP cocktail probe drugs consisting of phenacetin
(PNC), bupropion (BPP), losartan potassium (LK), omeprazole (OMP), dextromethorphan (DM), chlorzoxazone (CZZ) and midazolam (MDZ) and their respective metabolites in a single acquisition run and use this method to evaluate the influence of Zhuanggu Guanjie Pill (ZGGJP) on seven CYPs.
Methods: A cost-effective and simple UHPLC-(±)ESI-MS/MS method for simultaneous determination of seven probe drugs and metabolites in rat plasma was developed and validated. Male and female rats were randomly divided into three groups and treated with 1.2 g/kg/d ZGGJP, 5 g/kg/d ZGGJP
and 0.5% CMC-Na for 14 consecutive days. After 24 h of the last administration, all rats were administrated orally with probe drugs. The influence of ZGGJP on the CYPs was carried out by comparing the metabolic ratio (Cmax, AUC0-t) of metabolites/probe
drugs in rats. Results: The calibration curves were linear, with correlation coefficient > 0.99 for seven probe drugs and their corresponding metabolites. Intra- and inter-day precisions were not greater than 15% RSD and the accuracies were within ± 15% of nominal concentrations.
The ZGGJP showed significant inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats. Conclusion: ZGGJP had inductive effects on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.
研究领域:
药理学
·
临床药学
·
中药学
✓ 已验证
DOI
PubMed
高影响因子
BIOTECHNOLOGY LETTERS
·
2023
·Vol. 45
·期 8
·993-1000
·
IF 2.7
Peng Shuaiying,Chu Zhongmei,Lu Jianfeng,Li Dongxiao,Wang Yonghong,Yang Shengli,Zhang Yi
The self-sufficient cytochrome P450 BM3 mutant (A74G/F87V/D168H/L188Q) can serve as a biocatalyst for whole-cell catalysis process of indigo. Nevertheless, the bioconversion yield of indigo is generally low under normal cultivation conditions (37 °C, 250 rpm). In this study, a recombinant E. coli BL21(DE3) strain was constructed to co-express the P450 BM3 mutant gene and GroEL/ES genes to investigate whether GroEL/ES can promote the indigo bioconversion yield in E. coli . The results revealed that the GroEL/ES system could significantly increase the indigo bioconversion yield, and the indigo bioconversion yield of the strain co-expressing P450 BM3 mutant and GroEL/ES was about 21-fold that of the strain only expressing the P450 BM3 mutant. In addition, the P450 BM3 enzyme content and in vitro indigo bioconversion yield were determined to explore the underlying mechanism for the improvement of indigo bioconversion yield. The results revealed that GroEL/ES did not increase indigo bioconversion yield by increasing the content of P450 BM3 enzyme and its enzymatic transformation efficiency. Moreover, GroEL/ES could improve the intracellular nicotinamide adenine dinucleotide phosphate (NADPH)/NADP + ratio. Given that NADPH is an important coenzyme in the catalytic process of indigo, the underlying mechanism for the improvement of indigo bioconversion yield is probably related to an increase in the intracellular NADPH/NADP + ratio.
研究领域:
生物化学
·
生物技术
·
酶学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Ziqi Liang,Qiao Zhou,Yicheng Li,Xiaoqing Liu,Yiwen Shen,Jian Tian,Xiaolu Wang,Xing Qin,Yuan Wang,Huiying Luo,Xiaojun Yang,Bin Yao,Tao Tu
Cytochrome P450 enzymes (P450s) are promising candidates for the biosynthesis of 25-hydroxyvitamin D3 (25(OH)VD3). However, their industrial application is limited by challenges, such as low stability, inefficient catalysis, and uncoupling reactions. The construction of self-sufficient P450s offers a strategic solution to these limitations, but requires linker optimization to regulate interdomain conformational dynamics. In this study, we integrated whole-cell biocatalyst screening with systematic optimization of reaction conditions, including cosolvents, cell concentrations, and plasmid selection, to enhance catalytic performance. Under optimized conditions, the heme domain Vdh-K1 achieved a 91.6% conversion efficiency and was subsequently selected for chimeric enzyme assembly. By employing local energetic frustration analysis to evaluate protein flexibility and allosteric dynamics, we identified chimeric P450 variants with highly frustrated linkers. The optimal variant, VK1-CYP116B46-L21, exhibited improved thermostability, catalytic activity, and coupling efficiency, achieving a yield of 4.89 mM (1.96 g/L) 25(OH)VD3 in Escherichia coli whole-cell catalysis─the highest reported yield to date. This work underscores the utility of computational frustration analysis in refining linker dynamics for multidomain enzymes and establishes a scalable, cost-effective framework to advance P450s systems for industrial biosynthesis of high-value compounds.
研究领域:
生物化学
·
工业生物技术
·
酶工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2018
·Vol. 32
·期 8
·e4250
·
IF 1.688
Lin-Hu Ye,Xin-Qian Zhao,Ling-Ti Kong,Li-Sha Wang,Xue Tao,Hui Wu,Mei He,Qi Chang
Danhong Injection (DHI) as a Chinese patent medicine is mainly used to treat ischemic encephalopathy and coronary heart disease in combination with other chemotherapy. However, the information on DHI's potential drug interactions is limited. The goal of this work was to examine the potential P450-mediated metabolism drug interaction arising from DHI and its active components. The results showed that DHI inhibited CYP2C19, CYP2D6, CYP3A4, CYP2E1 and CYP2C9 with IC 50 values of 1.26, 1.42, 1.63, 1.10 and 1.67% ( v /v), respectively. Danshensu and rosmarinic acid inhibited CYP2E1 and CYP2C9 with IC 50 values of 36.63 and 75.76 μ m , and 34.42 and 76.89 μ m , respectively. Salvianolic acid A and B inhibited CYP2D6, CYP2E1 and CYP2C9 with IC 50 values of 33.79, 21.64 and 31.94 μ m , and 45.47, 13.52 and 24.15 μ m , respectively. The study provides some useful information for safe and effective use of DHI in clinical practice.
研究领域:
药理学
·
临床医学
·
中药学
✓ 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）