XENOBIOTICA
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2021
·
IF 1.908
Min Tian,Shenzhi Zhou,Wei Li,Jiaru Li,Lan Yang,Ying Peng,Jiang Zheng
Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant Aegle marmelos, with multiple pharmacological activities.As one component of several dietary supplements, AGL caused a series of acute and chronic liver injuries. Nevertheless, the mechanisms of AGL-induced hepatotoxicity remain unclear. This study was conducted to identify reactive metabolite(s), to determine related metabolic pathways, and define the possible association of the bioactivation with AGL cytotoxicity.A demethylation metabolite (M1) and a GSH conjugate (M2) were detected in rat liver microsomal incubations containing AGL and GSH. The two metabolites were both found in bile of rats and rat primary hepatocytes after AGL administration.Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalysing this metabolic activation.Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of AGL. The results suggest that AGL was metabolized to a p-quinone methide intermediate which could in part participate in AGL-induced cytotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Yingying Hu,Zhize Ye,Hualu Wu,Xiaohai Chen,Hailun Xia,Jian-ping Cai,Guo-xin Hu,Ren-ai Xu
Clothianidin , classified as a second-generation neonicotinoid , has achieved extensive application due to its high efficacy against insect pests . This broad-spectrum usage has resulted in its frequent detection in environmental surveys. CYP2C19 and CYP3A4 are crucial for converting clothianidin to desmethyl-clothianidin (dm-clothianidin). The expression of these CYP450s can be significantly influenced by genetic polymorphisms . The objective of our research was to examine the catalytic effects of 27 CYP3A4 variants and 31 CYP2C19 variants on the metabolism of clothianidin within recombinant insect microsomes . These variants were assessed through a well-established incubation procedure. In addition, the concentration of its metabolite dm-clothianidin was quantified by employing an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Lastly, the kinetic parameters of these CYP3A4 and CYP2C19 variants were calculated by applying Michaelis-Menten kinetic analysis to fit the data. The observed changes in enzyme activity were related to the metabolic transformation of clothianidin to dm-clothianidin. In the CYP2C19 metabolic pathway, one variant (CYP2C19.23) showed no notable change in intrinsic clearance (CL int ), four variants (CYP2C19.29, .30, .31 and L16F) demonstrated a marked increase in CL int (110.86–183.46 %), and the remaining 25 variants exhibited a considerable decrease in CL int (26.38–89.79 %), with a maximum decrease of 73.62 % (CYP2C19.6). In the CYP3A4 metabolic pathway, 26 variants demonstrated significantly reduced CL int (10.54–52.52 %), with a maximum decrease of 89.46 % (CYP3A4.20). Our results suggested that most variants of CYP3A4 and CYP2C19 significantly altered the enzymatic activities associated with clothianidin metabolism to various degrees. This study provides new insights into assessing the metabolic behavior of pesticides and delivers crucial data that can guide clinical detoxification strategies.
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
高影响因子
PHARMAZIE
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2014
·Vol. 69
·期 5
·362-366
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IF 1.003
Kong L.M.,Xu S.Y.,Hu H.H.,Zhou H.,Jiang H.D.,Yu L.S.,Zeng S.
The aim of the present study was to develop the recombinant insect cell-expressed protein as an in vitro model for inhibitors screening for human cytochrome P450 2C19 (CYP2C19), and to use the model to investigate the inhibition effect of three phytochemicals on CYP2C19 in
vitro. Omeprazole was applied as the probe substrate. The estimated inhibitory constant (Ki) of ticlopidine and fluvoxamine were 0.64 ± 0.025 M and 0.29 ± 0.090 M, respectively. After co-incubation with ticlopidine or fluvoxamine, the mean omeprazole Michaelis-Menten
constant (Km) increased from 4.99 ± 0.22 M to 16.25 ± 1.22 M or 19.20 ± 1.73 M, respectively, while omeprazole's mean Vmax did not vary much. Both ticlopidine and fluvoxamine were competitive inhibitors of CYP2C19. The IC50 of three phytochemicals,
isoalantolactone, curcumol and schisandrin A was determined as 38.91 M, 121.0 M and 86.41 M, and the Ki as 5.02 ± 1.04 M, 35.84 ± 8.95 M, and 4.46 ± 0.017 M, respectively. The in vitro model for inhibitor screening established using recombinant CYP2C19
could be used to assess the inhibition potential of drug candidates. Isoalantolactone and schisandrin A are potent inhibitors of CYP2C19, while curcumol is a moderate potent inhibitor of CYP2C19.
研究领域:
药理学
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分子生物学
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高影响因子
Micromachines
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2023
·Vol. 14
·期 3
·541
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IF 3.4
Siling Chen,Rongjun Yu,Ying Li,Jiangling Wu,Jingfu Qiu,Xinyi Huang,Jianjiang Xue
Currently, the therapeutic effect of clopidogrel differs considerably among individuals and is thought to be closely related to the genetic polymorphism ofCYP2C19. TheCYP2C19*2gene can reduce the antiplatelet aggregation effect of clopidogrel, which increases the risk of major cardiovascular adverse events in patients. In this research, we report a new type of biosensor for the highly sensitive detection of theCYP2C19*2gene based on exonuclease III assisted electric signal amplification and the use of calixarene to enrich electrical signal substances. Specifically, under the best conditions, the logarithmic concentrations of the analytes have a good linear relationship with the peak current in the range of 0.01 fM to 100 pM and the detection limit is 13.49 aM. The results have also shown that this method has good selectivity, high sensitivity, and stability, etc., and will provide a very promising application for the detection of theCYP2C19*2gene and other biological molecules by replacing corresponding nucleic acid sequences.Keywords:clopidogrel;CYP2C19*2gene;electrochemical biosensor;exonuclease III;calixarene
研究领域:
医学
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生物化学
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遗传学
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PubMed
高影响因子
MICROCHIMICA ACTA
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2023
·Vol. 190
·期 5
·1-10
·
IF 5.7
Ni Yun,Chen Xiu,Ling Chen,Zhu Ziye,Yue Yao,Wang Jie,He Aolin,Liu Ruijiang
The CYP2C19*2 gene carriers and non-carriers are closely related to the dosage of clopidogrel. To correctly guide the use of clopidogrel and promote individualized therapy, an ultra-sensitive electrochemical biosensor was developed for the detection of CYP2C19*2 gene. The heterogeneous α-Fe 2 O 3 /Fe 3 O 4 nanosheets were prepared via the hydrothermal-calcination process, and the preparation parameters were optimized. The average diameter and thickness of the nanosheets were approximately 150 nm and 53 nm, respectively; and the saturation magnetization was 80.2 emu/g. The α-Fe 2 O 3 /Fe 3 O 4 @Au nanosheets were prepared by sodium borohydride reduction method, and self-assembled to the electrode surface with magnetic field. Ultra-sensitive detection of CYP2C19*2 gene was realized through the recognition ability of strong single base mismatching of peptide nucleic acid and signal amplification effect of magnetic α-Fe 2 O 3 /Fe 3 O 4 @Au nanosheets. Under optimal detection conditions, the current had a good linear correlation with the negative logarithm of CYP2C19*2 gene concentration in the range 1 pM—1 nM, and the detection limit was 0.64 pM (S/N = 3). Meanwhile, the electrochemical signals of target DNA and incomplete complementary DNA were detected. The constructed biosensor exhibited good selectivity, reproducibility, and stability, providing a promising strategy for the detection of other gene mutations by electrochemical biosensors. Graphical Abstract
研究领域:
生物医学工程
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分子诊断学
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材料科学
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PubMed
高影响因子
Pharmacogenomics & Personalized Medicine
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2021
·
IF 3.912
Magesa Mafuru,Sanlan Wu,Henry Mayala,Zaituni Msengwa,Amani Phillip,Charles Mgone
Purpose To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders.Patients and Methods A prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient’s records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient.Findings Fifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-Ctrough, (4.31µg/mL [IQR, 1.64µg/mL–7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL–2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86µg/mL [IQR 1.33µg/mL–4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL–3.48µg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL–5µg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL–9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL–1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole.Conclusion Coadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.
研究领域:
药理学
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临床医学
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遗传学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
·
IF 3.8
Fei Gong,Huihui Hu,Ying Ouyang,Zheng-Zheng Liao,Ying Kong,Jin-Fang Hu,Hua He,Ying Zhou
The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC 0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC 0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus.
研究领域:
药理学
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临床医学
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遗传药理学
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
·
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
PHARMACOGENOMICS
·
2026
·
IF 1.6
Qinrong Lin,Wenfeng Xu,Qiaoling Zhang,Zebei Lu,Peiwu Geng,Chunhong Chen,Yuntong Ma,Aixia Han,Rucong Liu,Shangqing Wu,Jianping Cai,Pengfei Jin,Shuanghu Wang,Da-Peng Dai
Introduction The cytochrome P450 2C19 (CYP2C19) enzyme plays a critical role in the metabolism of several clinically important drugs, but the genetic polymorphisms of CYP2C19 have been partially characterized in the Chinese population.Methods Genomic DNA from 1210 Chinese Han individuals was subjected to next-generation sequencing to screen for CYP2C19 variants, and newly identified mutations were confirmed by Sanger sequencing. CYP2C19 microsomes were expressed in vitro using an insect cell expression system, and their metabolic activity toward (S)-mephenytoin was quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).Results Genetic screening of CYP2C19 gene in 1210 Chinese Han individuals was performed and identified 11 previously unreported variants. Recombinant expression of these novel variants in insect microsomes demonstrated that approximately half of the variants exhibited protein expression levels comparable to the wild type. Using (S)-mephenytoin as a probe substrate, in vitro metabolic activity assays revealed that five variants (G79X, D188fs, A297D, A297V, and T302R) exhibited abolished enzymatic activity, whereas the remaining variants showed significantly reduced activity compared to the wild-type enzyme.Conclusion This study reveals a high prevalence of functionally impaired rare CYP2C19 variants in the Chinese Han population, underscoring their potential clinical relevance for personalized medicine.
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高影响因子
DRUG METABOLISM AND DISPOSITION
·
2026
·
IF 4
Yan Zhang,Zihao Cheng,Jie Dai,Chunlei Zhang,Xueqian Cheng,Ying Peng,Weiwei Li,Jiang Zheng
Corydalis Decumbentis Rhizoma (CDR) is a traditional Chinese herbal medicine, which has been clinically used for treating migraine, relieving the symptoms of rheumatoid arthritis, and reversing osteoporosis. Bicuculline (BIC) is one of the main bioactive ingredients present in CDR. The purpose of this study was to comprehensively investigate the interaction of BIC with cytochrome P450 enzymes and the alteration of the pharmacokinetic properties of the active thiol metabolite 4 of clopidogrel when co-administered. BIC showed time-, concentration-, and NADPH-dependent inhibitory effects on CYP2C19. BIC (2.0 μM) inhibited CYP2C19 activity by about 64% after 9 min of incubation at 30 °C, and K I and k inact were 0.09 μM and 0.051 min -1 , respectively. Ticlopidine showed a significant protective effect against BIC-induced CYP2C19 inactivation. Dialysis did not restore the inhibited enzyme activity induced by BIC. Moreover, the addition of catalase/superoxide dismutase or glutathione (GSH) did not show protective effects against BIC-induced enzyme inactivation. It is speculated that carbene intermediates were involved in BIC-induced inactivation of CYP2C19, since K 3 Fe (CN) 6 restored the enzymatic activity. In addition, BIC and CDR extract pretreatment resulted in a significant decrease in the C max and AUC of the plasma thiol metabolite in rats given clopidogrel.
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高影响因子
XENOBIOTICA
·
2023
·
IF 1.8
Fengping Chen,Haizhu Zou,Ping Zhang,Yuqi Yan
In vitro metabolism of bicyclol was studied using liver microsomes, hepatocytes and human recombinant cytochrome P450 enzymes. Liquid chromatography-benchtop orbitrap mass spectrometry technique was utilised to identify the metabolites.A total of 19 metabolites, including 5 new metabolites (M2, M3, M4, M5 and M16) were tentatively identified. Among these metabolites, M6&M8 (demethylenation), M9&M10 (demethylation) and M19 (glucuronidation) were the major metabolites.In glutathione (GSH)-supplemented liver microsomes, 5 new GSH conjugates were found and tentatively identified. The formation was assumed to be through demethylenation of methylenedioxyphenyl to form catechol derivatives, which further underwent oxidation to form ortho-quinone intermediates, reacting with GSH to form stable adducts.CYP3A4 and 2C19 were demonstrated to be the major enzymes responsible for the bioactivation of bicyclol.This study provided valuable information on the metabolic fate of bicyclol in liver microsomes and hepatocytes, and the bioactivation pathways were reported for the first time, which would be helpful for us to understand the potential drug-drug interactions and the possible side effect of this drug.
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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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2021
·
IF 5.194
Shuaibing Liu,Ziteng Wang,Eric Chan,Yibo Zhao,Jian Kang,Xiaojian Zhang,Xin Tian
Vicagrel, an antiplatelet drug candidate targeting platelet P2Y 12 receptor and has finished its phase II clinical trial . The inhibition of six major cytochrome P450 enzymes (P450) (CYP2B6, CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 , and CYP3A4) and six UDP-glucuronosyltransferases (UGT) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) by vicagrel was evaluated using pooled human liver microsomes and specific probe substrates. Physiology-based pharmacokinetic (PBPK) simulation was further applied to predict the in vivo drug-drug interaction (DDI) potential between vicagrel and bupropion as well as S-mephenytoin. The results suggested that vicagrel inhibited CYP2B6 and CYP2C19 potently with apparent IC 50 values of 1.6 and 2.0 μM, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of CYP2B6-catalyzed bupropion hydroxylation and noncompetitive inhibition of CYP2C19-mediated S-mephenytoin 4′-hydroxylation with K i values of 0.19 μM and 1.2 μM, respectively. Vicagrel displayed profound time-dependent inhibition towards CYP2B6 with maximal rate constant of inactivation ( k inact ) and half-maximal inactivator concentration ( K I ) values of 0.062 min −1 and 1.52 μM, respectively. No time-dependent inhibition by vicagrel was noted for CYP2C19. For UGT, negligible to moderate inhibition by vicagrel was observed with IC 50 values of >50.0, >50.0, 28.2, 8.7, >50.0 and 28.2 μM for UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of UGT1A6-catalyzed N-Acetylserotonin β-D-glucuronidation with a K i value of 5.6 μM. No time-dependent inhibition by vicagrel was noted for UGT1A6. PBPK simulation indicated that neither altered AUC nor C max of bupropion and S-mephenytoin was observed in the presence of vicagrel. Our study provides inhibitory constants for future DDI prediction between vicagrel and drug substrates of CYP2B6, CYP2C19 and UGT1A6. In addition, our simulation suggests the lack of clinically important DDI between vicagrel and bupropion or S-mephenytoin.
研究领域:
药理学
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制药学
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临床试验
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）