CHEMICAL RESEARCH IN TOXICOLOGY
·
2021
·
IF 3.739
Yutong You,Xu Wang,Kaiqi Ma,Jiaru Li,Ying Peng,Jiang Zheng
Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX’s toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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肝脏病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Lin Fei,Lin Xinhua,Wang Xuewen,Mei Guanghui,Chen Bing,Yao Hong,Huang Lingyi
Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS.Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms.Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC50 ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC50 < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC50 < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes.Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.
研究领域:
药理学
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中药学
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代谢组学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 20
·期 1
·771-778
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IF 1.851
Yanyan Wang,Huaqiao Tang,Min Xu,Jie Luo,Ling Zhao,Fei Shi,Gang Ye,Cheng Lv,Yinglun Li
The aim of the present study was to evaluate the long‑term effect of copper nanoparticles (CuNPs) on cytochrome P450 (CYP450) enzymes in the rat brain. Rats were repeatedly gavaged with different forms of copper sources for 28 days, and the levels of oxidative stress and CYP450 mRNA and protein expression in the rat brain were subsequently analyzed. The results demonstrated that a high dose of CuNPs (200 mg/kg) induced severe oxidative stress in the rat brain along with a decrease in the levels of total superoxide dismutase and glutathione, and an increase in hydroxyl radicals and malondialdehyde. A medium dose of CuNPs reduced CYP450 2C11 and CYP450 3A1 protein expression in the rat brain, whereas high doses of CuNPs resulted in decreased expression of most CYP450 enzyme proteins, and inhibition of pregnane X receptor and constitutive androstane receptor expression. The results suggested that CuNPs may inhibit CYP450 enzyme expression by increasing the levels of oxidative stress and decreasing the expression of nuclear receptors in the rat brain, which affects the metabolism of drugs and endogenous hormones in the brain.
研究领域:
毒理学
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药理学
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神经科学
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PubMed
高影响因子
CHEMBIOCHEM
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2022
·Vol. 24
·期 3
·e202200529
·
IF 3.461
Yu Yan,Chenni Zheng,Wei Song,Jing Wu,Liang Guo,Cong Gao,Jia Liu,Xiulai Chen,Meng Zhu,Liming Liu
Graphical Based on the resolved crystal structure (PDB code: 7X53), a protein engineering strategy was developed in CYP238A1 and an optimal CYP238A1 NPV variant containing a local hydrophobic “fence” at the active site was obtained, which increased the H 2 O 2 -dependent norbornene (NBE) epoxidation activity by 7.5-fold compared with that of CYP238A1 WT and switched the monooxygenase mode to the peroxygenase mode. Epoxy-norbornane (EPO-NBE) is a crucial building block for the synthesis of various biologically active heterocyclic systems. To develop an efficient protocol for producing EPO-NBE using norbornene (NBE) as a substrate, cytochrome P450 enzyme from Pseudomonas putida (CYP238A1) was examined and its crystal structure (PDB code: 7X53) was resolved. Molecular mechanism analysis showed a high energy barrier related to iron-alkoxy radical complex formation. Therefore, a protein engineering strategy was developed and an optimal CYP238A1 NPV variant containing a local hydrophobic “fence” at the active site was obtained, which increased the H 2 O 2 -dependent epoxidation activity by 7.5-fold compared with that of CYP238A1 WT . Among the “fence”, Glu255 participates in an efficient proton transfer system. Whole-cell transformation using CYP238A1 NPV achieved an EPO-NBE yield of 77.6 g ⋅ L −1 in a 30-L reactor with 66.3 % conversion. These results demonstrate the potential of this system for industrial production of EPO-NBE and provides a new biocatalytic platform for epoxidation chemistry.
研究领域:
生物化学
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生物技术
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酶学
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化工
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分子生物学
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DOI
PubMed
高影响因子
XENOBIOTICA
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2026
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IF 1.5
Jia-ou Chen,Ling-li Zhou,Jian-heng Lin,Hao-tian Zhou,Lai-fang Sun,Cheng-ke Huang
1. This study aims to investigate the effects of orally administered paeoniflorin (PF), a major bioactive compound from Paeonia lactiflora, on cytochrome P450 (CYP450) enzyme activity in rats to assess potential drug-drug interactions (DDIs). Following PF treatment, rats received a mixed probe drug solution containing phenacetin (PHE), tolbutamide (TOL), omeprazole, and metoprolol, and plasma concentrations of the substrates and metabolites were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry. The metabolic ratio, calculated as the ratio of metabolite to parent drug area under the curve (AUC), was used to evaluate CYP activity.2. Results showed that AUCAcetaminophen/AUCPHE values were significantly elevated in PF-treated groups, indicating induction of CYP1A2, whereas AUCOHTOL/AUCTOL values were significantly reduced, suggesting inhibition of CYP2C11. No significant effects were observed on CYP2C or CYP2D2 activities.3. These findings indicate that PF can modulate CYP1A2 and CYP2C11 activities under the experimental conditions tested, as assessed using PHE and TOL as functional markers. However, the magnitude of these effects was modest and observed only at relatively high PF doses (50 and 100 mg/kg). Given the inherent species differences between rat and human CYP enzymes, direct extrapolation of these findings to human CYP1A2 and CYP2C11 requires further validation in human-relevant models.
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PubMed
高影响因子
TOXICOLOGY IN VITRO
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2025
·
IF 2.7
Xiu Chen,Xiaoyi Pan,Jieping Zhao,Huihui Jin,Hengbin Zhang,Yongbiao Song,Hui Zhou,Jianbiao Yao,Huidi Jiang
Neocryptotanshinone (NCTS), an ingredient of Salviae Miltiorrhizae Radix et Rhizoma, is a promising compound for development since it exhibits various pharmacological effects including hypoglycemic and anti-inflammatory activities. In this study, we aimed to elucidate the interactions between NCTS and cytochrome P450s (CYPs), including the CYP-mediated NCTS metabolism and NCTS-induced CYP regulation. The results revealed that NCTS was mainly metabolized by CYPs in human liver microsomes (HLMs), and CYP2C8 and 2C9 were identified as the main CYPs involved; the relative contributions of CYP2C8 and 2C9 were 35 % and 65 %, respectively, after normalization of individual CYP abundance in the human liver. Meanwhile, NCTS weakly inhibited CYP1A2, 2C8, and 2C9, with IC 50 > 30 μM. In addition, NCTS induced CYP2B6 and CYP3A4 expression in human primary hepatocytes, and the underlying mechanism was found by the activation of the pregnane X receptor (PXR) vis reporter gene assay. Molecular docking of NCTS and CYPs, PXR confirmed these results. Our study sheds light on the interactions of NCTS with CYPs and provides useful information for predicting potential drug-drug interactions for NCTS, which will be helpful for NCTS development and clinical utilization of drugs containing NCTS.
研究领域:
药理学
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药物代谢
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分子生物学
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生物信息学
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毒理学
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DOI
PubMed
高影响因子
PLANTA
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2022
·Vol. 256
·期 3
·1-17
·
IF 4.54
Han Xinpei,Xing Yadi,Zhu Yaqian,Luo Lei,Liu Lulu,Zhai Yaohua,Wang Wenjing,Shao Ruixing,Ren Maozhi,Li Fuguang,Yang Qinghua
Main conclusion GhMYC2 regulates the gossypol biosynthesis pathway in cotton through activation of the expression of gossypol synthesis gene CYP71BE79 , CDNC , CYP706B1 , DH1 , and CYP82D113. Abstract Cotton is one of the main cash crops globally. Cottonseed contains fiber, fat, protein, and starch, and has important economic value. However, gossypol in cottonseed seriously affects the development and utilization of cottonseed. Nonetheless, gossypol has great application potential in agriculture, medicine, and industry. Therefore, it is very important to study gossypol biosynthesis and its upstream regulatory pathways. It has been reported that the content of gossypol in hairy roots of cotton is regulated through jasmonic acid signaling; however, the specific molecular mechanism has not been revealed yet. We found that the expression of basic helix–loop–helix family transcription factor GhMYC2 was significantly upregulated after exogenous administration of methyl jasmonate to cotton seedlings, and the content of gossypol changed significantly with the variation of GhMYC2 expression. Further studies revealed that GhMYC2 could specifically bind to the G-Box in the promoter region of CDNC , CYP706B1 , DH1 , CYP82D113 , CYP71BE79 to activate its expression and regulate gossypol synthesis, and its activation of CYP71BE79 promoter was inhibited by GhJAZ2 . Not only that GhMYC2 could also interact with GoPGF . In this work, the molecular mechanisms of gossypol biosynthesis regulated by GhMYC2 were analyzed. The results provide a theoretical basis for cultivating new varieties of low-gossypol or high-gossypol cotton and creating excellent germplasm resources.
研究领域:
植物科学
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分子生物学
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农业科学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2016
·
IF 3.055
Lifeng Niu,Lina Ding,Chunyun Lu,Feifei Zuo,Ke Yao,Shaobo Xu,Wen Li,Donghua Yang,Xia Xu
Ethnopharmacological relevance Flavokawain A, the major chalcone in kava extracts , was served as beverages for informal social occasions and traditional ceremonials in most South Pacific islands. It exhibited strong antiproliferative and apoptotic effects against human prostate and urinary bladder cancer cells. Aim of the study The current study was purposed to investigate the interaction between Flavokawain A and Cytochrome P450 , including the inhibitory effects of Flavokawain A on predominant CYP450 isotypes and further clarified the inhibitory mechanism of FKA on CYP450 enzymes. Besides, study about identifying the key CYP450 isotypes responsible for the metabolism of FKA was also performed. Materials and methods In this study, probe-based assays with rat liver microsome system were used to characterize the inhibitory effects of FKA. Molecular docking study was performed to further explore the binding site of FKA on CYP450 isoforms. In addition, chemical inhibition experiments using specific inhibitors (a-naphthoflavone, quinidine , sulfamethoxazde, ketoconazole, omeprazole) were performed to clarify the individual CYP450 isoform that are responsible for the metabolism of FKA. Results FKA showed significant inhibition on CYP1A2 , CYP2D1 , CYP2C6 and CYP3A2 activities with IC 50 values of 102.23, 20.39, 69.95, 60.22 μmol/L, respectively. The inhibition model was competitive, mixed-inhibition, uncompetitive, and noncompetitive for CYP1A2, CYP2D1, CYP2C6 and CYP3A2 enzymes. Molecular docking study indicated the ligand-binding conformation of FKA in the active site of CYP450 isoforms. The chemical inhibition experiments showed that the metabolic clearance rate of Flavokawain A decreased to 19.84%, 50.38%, and 67.02% of the control in the presence of ketoconazole, sulfamethoxazde and a-naphthoflavone. Conclusion The study showed that Flavokawain A has varying inhibitory effect on CYP450 enzymes and CYP3A2 was the principal CYP isoform contributing to the metabolism of Flavokawain A. Besides, CYP2C6 and CYP1A2 isoforms also play important roles in the metabolism of FKA. Our results provided a basis for better understanding the biotransformation of FKA and prediction of drug-drug interaction of FKA.
研究领域:
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
PHARMAZIE
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2012
·Vol. 67
·期 12
·1002-1006
·
IF 1.006
Dong Rui-Hua,Fang Zhong-Ze,Zhu Liang-Liang,Ge Guang-Bo,Cao Yun-Feng,Li Xiao-Bao,Hu Cui-Min,Yang Ling,Liu Ze-Yuan
Carvacrol and thymol are phenolic compounds with similar structures isolated from many aromatic plants, and have been demonstrated to exert multiple pharmacological effects. The metabolic and pharmacokinetic behaviour of thymol and carvacrol has received much attention. Carvacrol and
thymol have been demonstrated to undergo phase I metabolism such as hydroxylation reaction. However, drug-metabolizing enzymes involved in this process remain unclear. Given that cytochrome P450 s (CYPs) are involved in most phase I metabolism, the aim of the present study was to investigate
the role of CYPs in the metabolism of thymol and carvacrol. After incubation with human liver microsomes (HLMs) in the presence of NADPH, a new metabolite and two metabolites were detected for thymol and carvacrol, respectively. A combination of chemical inhibition studies and assays with
recombinant CYP isoforms demonstrated that CYP2A6 was the predominant drug-metabolizing enzyme involved in the metabolism of thymol and carvacrol. All these results remind the researchers that special attention should be paid on pharmacokinetic and clinical outcomes when thymol or carvacrol
was co-administrated with other compounds mainly undergoing CYP2A6-mediated metabolism.
研究领域:
药理学
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生物化学
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产品关联
DOI
高影响因子
Chinese Journal of Natural Medicines
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2020
·
IF 2.014
Yong-Jiang WANG,Li WANG,Xin HE,Dong-Dong XU,Jun TANG,Ya-Tuan MA,Yi-Jun YAN,Yu-Cheng GU,Jing YANG,Sheng-Xiong HUANG
Inthomycins are polyketide antibiotics which contain a terminal carboxamide group and a triene chain. Inthomycin B ( 1 ) and its two new analogues 2 and 3 were isolated from the crude extract of Streptomyces pactum L8. Identification of the gene cluster for inthomycin biosynthesis as well as the 15 N -labeled glycine incorporation into inthomycins are described. Combined with the gene deletion of the rare P450 domain in the NRPS module, a formation mechanism of carboxamide moiety in inthomycins was proposed via an oxidative release of the assembly chain assisted by the P450 domain.
研究领域:
微生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Kun Ren,Xuanmeng Zhang,Ruijie Wang,Shumeng Ren,Huiming Hua,Dongmei Wang,Yingni Pan,Xiaoqiu Liu
Ethnopharmacological relevance Euodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice. Aim of the study This study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage. Materials and methods Male C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats. Results The intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria , inhibiting the metabolic activation of EF and alleviating hepatotoxicity. Conclusions By combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.
研究领域:
药理学
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毒理学
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中医药学
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PubMed
高影响因子
Metabolites
·
2019
·Vol. 9
·期 4
·77
·
IF 3.303
Xiao Pu,Yiqiao Gao,Ruiting Li,Wei Li,Yuan Tian,Zunjian Zhang,Fengguo Xu
Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism.Keywords:CYP1A2;endogenous biomarkers;metabolomics;branched-chain amino acids;phenylalanine;tyrosine
研究领域:
药理学
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生物化学
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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）