CHEMICO-BIOLOGICAL INTERACTIONS
·
2014
·
IF 2.982
Qi Shen,Minjuan Zuo,Li Ma,Ye Tian,Lu Wang,Huidi Jiang,Quan Zhou,Hui Zhou,Lushan Yu,Su Zeng
Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbo nucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H] + ions at m / z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para -methylene phenol and results from a product ion scan, GSH tends to conjugate with C9’ after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l -buthionine sulfoximine or N -acetyl- l -cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC 50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-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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肿瘤学
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酶学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2020
·
IF 4.236
Zhang Lu-Lu,Huang Wen,Zhang Ying-Ying,Fan Gang,He Jin,Ren Jing-Nan,Li Zhi,Li Xiao,Pan Si-Yi
α-Terpineol has been widely used in daily chemical, pharmaceutical, food, and flavor industries due to its pleasant odor with high economic value and pharmacological action. Our previous study showed that Penicillium digitatum DSM 62840 was an efficient biocatalyst for the transformation of limonene to α-terpineol. Thus, it was meaningful to explore the genome features and the gene expression differences of strain DSM 62840 during limonene biotransformation, and the detailed bioconversion pathways. In this study, the functional genes related to limonene bioconversion were investigated using genome and transcriptome sequences analysis. The results showed that the P. digitatum DSM 62840 genome was estimated to be 29.09 Mb and it encoded 9,086 protein-encoding genes. The most annotated genes were associated to some protein metabolism and energy metabolism functions. When the threshold for differentially expressed genes (DEGs) was set at twofold ratio, a total of 4,128, and 4,148 DEGs were identified in P_L_12h (limonene-treated condition) compared with P_0h (blank) and P_12h (limonene-untreated blank), respectively. Among them, the expression levels of genes involved in the biosynthesis of secondary metabolites, energy metabolism and ATP-binding cassette (ABC) transporters were significantly altered during the biotransformation. And the reliability of these results was further confirmed by quantitative real-time polymerase chain reaction (RT-qPCR). Moreover, we found that the enzyme participated in limonene biotransformation was inducible. This enzyme was located in the microsome, and it was inhibited by cytochrome P450 inhibitors. This indicated that the cytochrome P450 may be responsible for the limonene bioconversion. Several differentially expressed cytochrome P450 genes were further identified, such as PDIDSM_85260 and PDIDSM_67430, which were significantly up-regulated with limonene treatment. These genes may be responsible for converting limonene to α-terpineol. Totally, the genomic and transcriptomic data could provide valuable information in the discovery of related-genes which was involved in limonene biotransformation, pathogenicity of fungi, and investigation of metabolites and biological pathways of strain DSM 62840.
研究领域:
微生物学
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基因组学
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分子生物学
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生物技术
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生物化学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2017
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IF 4.44
Zhaoyu Wang,Yao Lan,MingHao Chen,Cailing Wen,Yanxian Hu,Zhongqiu Liu,Ling Ye
Acetaminophen (APAP) is one of the most commonly used oral analgesics and antipyretics, but hepatotoxicity including liver failure may occur after overdose. The therapeutic options for treating APAP hepatotoxicity are limited. Eriodictyol, a dietary flavonoid with anti-inflammatory and antioxidant properties, was used here to determine its protective effects against APAP-induced hepatotoxicity in mice. Various administration routes and pharmacokinetics–pharmacodynamics (PK–PD) analyses were used to determine these effects. Protective effects were observed in intravenously and intraperitoneally but not in intragastrically administered eriodictyol. LC-MS/MS analysis revealed two monoglucuronide metabolites of eriodictyol in liver and intestine microsomes. Recombinant human uridine-5′-diphospho -glucuronosyltransferase (UGT) isoforms and chemical inhibition studies demonstrated that UGT1As (mainly UGT1A1, UGT1A9, UGT1A10) and UGT2B7 were likely the main contributors to eriodictyol glucuronidation. Intragastric administration of eriodictyol, which displayed lower parent and higher metabolite concentrations in the plasma, did not elicit protective effects against APAP hepatotoxicity, when compared to the intraperitoneal injection of eriodictyol. The relative bioavailability of eriodictyol was increased to 216.84% with the coadministration of glycyrrhetinic acid (GA), an inhibitor of UGT1As. Intragastric administration of eriodictyol in combination with GA also induced protective effects against APAP hepatotoxicity. Furthermore, intragastric administration of eriodictyol attenuated APAP hepatotoxicity in heterozygous Ugt1 (Ugt1+/−) mice but not in its wild-type littermates. Thus, UGT1A-mediated metabolic inactivation reduced the protective effect of eriodictyol. Eriodictyol attenuated APAP hepatotoxicity via inhibition of hepatic cytochrome P450 (cyp) 2e1 and cyp3a11 activities; reserve of glutathione (GSH) by improvement of glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glutathione S-transferase (GST) activities; elevation of superoxide dismutase (SOD) activity; and reduction of malondialdehyde (MDA) level. Our findings indicate that parenterally administered eriodictyol may be used to treat APAP-induced hepatotoxicity, and its efficacy can be enhanced by UGT1As down-regulation.
研究领域:
药理学
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毒理学
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代谢
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药物研发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2025
·
IF 4.3
Ping Zhu,Minxin Qin,Xinyu Wang,Qiang Gao,Dan Liu,Miaomiao Nie,Junmei Jia,Delin Qi,Cunfang Zhang
Microplastics (MPs) and antibiotics (ATs) accumulating in Qinghai Lake threaten aquatic health, yet their impact on Gymnocypris przewalskii ( G.przewalskii ) remains unclear.This multi-omics study investigated polypropylene MPs (PP-MPs) and sulfonamide antibiotics (SGD) on G.przewalskii. Groups included control group (C), single exposure groups (1 g/L SGD, 1 mg/L PP-MPs, 5 mg/L PP-MPs), and co-exposure groups (1 mg/L PP-MPs + 1 g/L SGD, 5 mg/L PP-MPs + 1 g/L SGD) exposed for 28 days. Using 16S rRNA sequencing, UHPLC, and MS/MS, we analyzed changes in the intestinal microbiota, metabolome, and transcriptome of G. przewalskii . Compared to control gruop, intestinal microbiota alpha diversity changed significantly in all treatments. The SGD group decreased notably, while co-exposure groups (SPL) showed significantly lower alpha diversity than single exposures. SPL groups exhibited higher beta diversity than controls and single exposures. In SPL, genera like Legionella, Fusobacterium, Phascolarctobacterium , and Bacteroides decreased, whereas Shinella, Lactobacillus , and Prevotella increased. Differential metabolites and genes decreased with rising concentrations across exposure groups. Most metabolites enriched in the ABC transporter pathway. Differentially expressed genes primarily enriched in carbon metabolism and cytochrome P450 pathways. Correlation analysis identified pathways like Neisseriaceae and Acinetobacter affecting Bilirubin in the gut, which in turn influenced liver genes LOC107556838, LOC109072261 and notum1a . This demonstrated G. przewalskii adaptation to PP-MPs and SGD through the gut-live. The study provides a scientific basis for protecting G. przewalskii and assessing health risks of MPs and ATs to aquatic ecosystems on the Qinghai-Tibet Plateau.
研究领域:
水生毒理学
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环境科学
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微生物学
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代谢组学
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转录组学
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生态毒理学
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鱼类生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Qiao-Lai Wang,Pei-Xi Zhang,Rui Shen,Meng Xu,Liang Han,Xuan Shi,Zi-Rui Zhou,Jing-Yi Yang,Jie-Qing Liu
Ethnopharmacological relevance Arbutin is a naturally occurring glucoside extracted from plants, known for its antioxidant and tyrosinase inhibiting properties. It is widely used in cosmetic and pharmaceutical industries. With in-depth study of arbutin, its application in disease treatment is expanding, presenting promising development prospects. However, reports on the metabolic stability, plasma protein binding rate, and pharmacokinetic properties of arbutin are scarce. Aim of the study The aim of this study is to enrich the data of metabolic stability and pharmacokinetics of arbutin through the early pre-clinical evaluation, thereby providing some experimental basis for advancing arbutin into clinical research. Materials and methods We developed an efficient and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determining arbutin in plasma. We investigated the metabolic and pharmacokinetic properties of arbutin through in vitro metabolism assay, cytochrome enzymes P450 (CYP450) inhibition studies, plasma protein binding rate analysis, Caco-2 cell permeability tests, and rat pharmacokinetics to understand its in vivo performance. Results In vitro studies show that arbutin is stable, albeit with some species differences. It exhibits low plasma protein binding (35.35 ± 11.03% ∼ 40.25 ± 2.47%), low lipophilicity, low permeability, short half-life (0.42 ± 0.30 h) and high oral bioavailability (65 ± 11.6%). Arbutin is primarily found in the liver and kidneys and is eliminated in the urine. It does not significantly inhibit CYP450 up to 10 μM, suggesting a low potential for drug interactions. Futhermore, preliminary toxicological experiments indicate arbutin's safety, supporting its potential as a therapeutic agent. Conclusion This study provides a comprehensive analysis the drug metabolism and pharmacokinetics (DMPK) of arbutin, enriching our understanding of its metabolism stability and pharmacokinetics properties, It establishes a foundation for further structural optimization, pharmacological studies, and the clinical development of arbutin.
研究领域:
药理学
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分析化学
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临床前研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Xiaoyue Yu,Jinqiu Sun,Yongjie Yang,Jianping Zhang,Yongliang Lu,Wei Tang
This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.
研究领域:
植物科学
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杂草科学
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分子生物学
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遗传学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Wenmin Li,Yikun Zan,Tong Wu,Sa Yang,Linlin Liu,Shanshan Li,Pingli Dai,Jing Gao
Chlorantraniliprole (CAP), a diamide insecticide, is extensively applied to combat pests in various crops. However, the widespread use of insecticides has raised concerns about their potential impact on pollinators. In the present study, we explored the toxic effects of CAP in two important honey bee species, Apis mellifera and Apis cerana . The 48 h LC 50 values of CAP for A. mellifera and A. cerana was 256.052 mg/L and 109.709 mg/L, implying that A. cerana is more sensitive to CAP. Prolonged exposure to 40 mg/L CAP significantly impaired sucrose responsiveness and climbing activity in both bee species. Both species showed a decrease in GR activity and GSH content with increasing CAP concentration. By contrast, the activities of GST, CAT, P450 and NAD-MDH were increased in both A. mellifera and A. cerana , but the differences between the 10 mg/L and 40 mg/L treatments were less pronounced in A. mellifera . Moreover, the immune related genes exhibited differential responses to CAP when comparing the two species. Low CAP concentrations led to down-regulation in expression of toll but up-regulation in expression of apideacin and hymeopatecin in A. mellifera , whereas A. cerana exhibited minimal changes in these genes. Additionally, CAP significantly inhibited the expression of ER stress response genes gp - 93 and P58 in A. mellifera , while 10 mg/L of CAP promoted P58 expression in A. cerana . Our results highlight species-specific effects with the possible, distinct detoxification mechanisms and immune responses between A. mellifera and A. cerana . These findings serve as a foundation for further evaluating the safety of CAP for honey bee species and offer insights into the scientific use of pesticides.
研究领域:
昆虫学
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毒理学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Min Liao,Minghao Jiang,Xumiao Wang,Wei Hu,Ning Zhao,Haiqun Cao
Acetyl-CoA carboxylase (ACCase)-inhibiting herbicides are among the most commonly used herbicides to control grassy weeds, especially Leptochloa chinensis , in rice fields across China. Herein, we collected a suspected resistant (R) population of L. chinensis (HFLJ16) from Lujiang county in Anhui Province. Whole plant dose response tests showed that, compared with the susceptible (S) population, the R population showed high resistance to cyhalofop-butyl (22-fold) and displayed cross-resistance to metamifop (9.7-fold), fenoxaprop- P -ethyl (18.7-fold), quizalofop- P -ethyl (7.6-fold), clodinafop-propargyl (12-fold) and clethodim (8.4-fold). We detected an amino acid substitution (Cys-2088-Arg) in the ACCase of resistant L. chinensis . However, ACCase gene expression levels were not significantly different ( P > 0.05) between R plants and S plants, without or with cyhalofop-butyl treatment. Furthermore, pretreatment with piperonyl butoxide (PBO, a cytochrome P450 monooxygenase (CYP450) inhibitor) or 4-chloro-7-nitrobenzoxadiazole (NBD-Cl, a glutathione-S-transferase (GST) inhibitor), inhibited the resistance of the R population to cyhalofop-butyl significantly (by approximately 60% and 26%, respectively). Liquid chromatography tandem mass spectrometry analysis showed that R plants metabolized cyhalofop-butyl and cyhalofop acid (its metabolite) significantly faster than S plants. Three CYP450 genes, one GST gene, and two ABC transporter genes were induced by cyhalofop-butyl and were overexpressed in the R population. Overall, GST-associated detoxification, CYP450 enhancement, and target-site gene mutation are responsible for the resistance of L. chinensis to cyhalofop-butyl.
研究领域:
植物科学
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分子生物学
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杂草科学
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除草剂抗性
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产品关联
DOI
PubMed
高影响因子
Reproductive Sciences
·
2024
·
IF 2.6
Zhou Nan,Lv Wenqiang,Chen Linna,Chen Kexin,He Qing,Xie Guangyan,Ma Jiachen,Cao Yijuan,Zhang Bei,Zhou Xueyan
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS. Graphical Abstract
研究领域:
内分泌学
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药理学
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生殖生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2019
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IF 7.149
Jian Zhou,Zhengshuang Yang,Qing Liu,Yiman Liu,Menglin Liu,Tiecheng Wang,Lingyan Zhu
As emerging alternatives of legacy perfluoroalkyl substances, perfluorophosphinates (PFPiAs) and perfluorophosphonates (PFPAs) are widely applied in industrial and agricultural fields and are supposed to be large partitioned to soil and highly persistent. It is of particular interest to understand their transfer from roots to shoots and transformation in plants, such as wheat. The results of hydroponic experiments indicated that C6/C6 PFPiA, C8/C8 PFPiA, perfluorooctanophosphonic acid (PFOPA), and perfluorohexaphosphonic acid (PFHxPA) were quickly adsorbed on the epidermis of wheat root (Triticum aestivum L.), which was driven by their hydrophobicity. A small fraction of the accumulated PFPiAs and PFPAs in the wheat root was subjected to absorption via an active process dependent on H+-ATPase. PFHxPA, which has the smallest molecular weight and medium hydrophilicity (log Kow < 4), displayed the strongest absorption efficiency via the water and anion channels and had the highest translocation potential from roots to shoots in wheat. C6/C6 and C8/C8 PFPiAs experienced phase I metabolism in wheat, although at a low rate, to form more persistent PFHxPA and PFOPA, respectively, as well as 1H-perfluorohexane (1H-PFHx) and 1H-perfluorooctane (1H-PFO), which were regulated by cytochrome P450 in wheat root. As a result, exposure to PFPiAs in roots ultimately caused the accumulation of more persistent PFPAs in the above-ground parts of plants, raising concerns on their potential risks on human health.
研究领域:
环境科学
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植物生理学
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毒理学
✓ 已验证
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2024
·Vol. 52
·期 8
·911-918
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IF 4.4
Jingyu Zhang,Weiwei Li,Ying Liu,Yan He,Zihao Cheng,Ximei Li,Yu Chen,Aihua Zhang,Ying Peng,Jiang Zheng
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for cytochrome P450 (CYP) s3A, 2C6, 2D, 2C11, 1A, and 2E, were selected as probe drugs for the pharmacokinetic study. Significant decreases in areas under the curves of probe substrates were observed in rats after consecutive 30-day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little change in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug–drug interactions.
研究领域:
毒理学
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药理学
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药学
✓ 已验证
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
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2025
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IF 4
Xiyue Huang,Lei Zhou,Huixian Chen,Xiaowei Sun,Mengyi Cao,Yangming Zhang,Dewen Li,Xuelin Zhu,Fajun Nan,Xiaoyan Chen
Hydroxamic acid is an excellent metal ion chelating group and is used commonly in the design of histone deacetylase (HDAC) inhibitors. Despite its utility, the hydroxamic acid group suffers from poor metabolic stability and undergoes rapid conversion to carboxylic acid, a process that has generally been described as hydrolytic metabolism. By using the HDAC inhibitor, bisthianostat as a model drug, this study provided novel insights into the role of cytochrome P450 (P450) enzymes in the metabolism of the hydroxamic acid group into the carboxylic acid metabolite (M351). The primary formation of M351 was observed in liver microsomes after incubating bisthianostat with different human liver, intestinal and plasma fractions. Chemical inhibition experiments further indicated that P450 enzyme-mediated oxidation was the main pathway for generation of M351, with hydrolysis making a minor contribution. 18 O-labeling isotope experiments and Griess assays demonstrated that the peroxoferric species of P450 enzymes acted as a nucleophile, attacking the carbonyl carbon of hydroxamic acid, leading to the formation of carboxylic acid and reactive nitrogen species. The metabolism of eight hydroxamic acid derivatives in human liver microsomes indicated that P450 enzymes exhibited substrate specificity in catalyzing the conversion of hydroxamic acids to carboxylic acids. Molecular docking results further revealed that oxidative metabolism occurred when the hydroxamic acid group was in appropriate proximity to the P450 catalytic center. Overall, this study demonstrated the important role of P450 enzymes in hydroxamic acid metabolism and provided valuable insights for future rational design and clinical applications of hydroxamic acid-based drugs.
研究领域:
药理学
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生物化学
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药物代谢
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酶学
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分子生物学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）