Food & Function
·
2025
·
IF 5.4
Hailing Song,Yun Ma,qian Du,Zeyuan Deng,Yalun Zou,Yadong Miao,Jing Li,Liufeng Zheng
Methionine-containing cyclolinopeptide ([1–9-NαC]-linusorb B2, CLB) and α-linolenic acid (ALA), two anti-inflammatory flaxseed constituents, were investigated for their combined vascular benefits. CLB-enriched orbitides were prepared for long-term high-fat diet (HFD)-fed mouse studies, while high-purity CLB monomer (>97%) was isolated via preparative chromatography for acute in vivo and cell-based assays. Structural confirmation and purity validation were achieved via mass spectrometry and liquid chromatography. CLB-enriched orbitides co-administered with ALA in HFD-fed mice reduced body weight gain, serum trimethylamine N-oxide (TMAO), dyslipidemia, and vascular inflammation, histologically confirmed by reduced pro-inflammatory mediators and endothelial repair. Purified CLB combined with ALA further demonstrated efficacy in alleviating TMAO-induced acute vascular inflammation in mice. Mechanistically, CLB enhanced ALA metabolism by upregulating key enzymes (lipoxygenases and cytochrome P450) and directly binding to their catalytic pockets. Combined effect loss upon enzyme inhibition confirmed ALA metabolic modulation as the key mechanism. These findings highlight CLB's role in amplifying ALA's efficacy to combat vascular inflammation.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Shuaibing Liu,Jinxin Miao,Hang Li,Guangbo Ge,Quanjun Yang,Songfeng Zhao,Cheng Guo
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, ultimately leading to liver dysfunction. The role of peroxisome proliferator-activated receptor α (pparα) in regulating hepatic drug-metabolizing enzymes, including cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs), in PSC remains insufficiently understood. In this study, wild-type and pparα −/− Syrian hamsters were used to establish a PSC model, aiming to investigate the effects of pparα on the expression and activity of P450 and UGT enzymes. Sequential windowed acquisition of all theoretical fragment ions profiling and multiple reaction monitoring mass spectrometry with high resolution assays revealed a significant downregulation of CYP2C27 and CYP2D20 in pparα−/− hamsters. Enzymatic kinetic assays demonstrated reduced activity for several enzymes, including CYP1A2 (involved in the metabolism of acetaminophen), CYP2C family (responsible for 4′-hydroxy diclofenac formation), CYP2D family (involved in dextrorphan production), CYP2E1 (involved in 6-hydroxy chlorzoxazone production), and UGTs (responsible for chenodeoxycholic acid 24-acyl-β-D-glucuronide and mycophenolic acid glucuronide formation). These reductions suggest impaired drug metabolism and an increased risk of drug-drug interactions in conditions of reduced pparα function. In contrast, enzymes such as the CYP2B family, CYP3A family, and UGTs involved in N-Acetyl serotonin β-D-glucuronide formation retained their activity, indicating selective pathway preservation in pparα −/− hamsters. These findings highlight the selective regulatory roles of pparα on certain drug-metabolizing enzymes, providing important insights into metabolic regulation in pparα-deficient states.
研究领域:
肝脏病学
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分子药理学
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药物代谢
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毒理学
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代谢调控
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实验动物模型
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转录调控
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高影响因子
ARCHIVES OF MICROBIOLOGY
·
2023
·Vol. 205
·期 7
·1-12
·
IF 2.8
Meng Min,Zhai Zhaochi,Zhang Zhenxing,Kim Jeonghan,Zhu Yongzhe
In this study, the metabolic pathway of the phenylpyrazole insecticide fipronil in Cunninghamella elegans ( C. elegans ) was investigated. Approximately 92% of fipronil was removed within 5 days, and seven metabolites were accumulated simultaneously. The structures of the metabolites were completely or tentatively identified by GC–MS and 1 H, 13 C NMR. To determine the oxidative enzymes involved in metabolism, piperonyl butoxide (PB) and methimazole (MZ) were used, and the kinetic responses of fipronil and its metabolites were determined. PB strongly inhibited fipronil metabolism, while MZ weakly inhibited its metabolism. The results suggest that cytochrome P450 (CYP) and flavin-dependent monooxygenase (FMO) may participate in fipronil metabolism. Integrated metabolic pathways can be inferred from the control and inhibitor experiments. Several novel products from the fungal transformation of fipronil were identified, and similarities between C. elegans transformation and mammalian metabolism of fipronil were compared. Therefore, these results will help to gain insight into the fungal degradation of fipronil and potential applications in fipronil bioremediation. At present, microbial degradation of fipronil is the most promising approach and maintains environmental sustainability. In addition, the ability of C. elegans to mimic mammalian metabolism will assist in illustrating the metabolic fate of fipronil in mammalian hepatocytes and assess its toxicity and potential adverse effects.
研究领域:
环境科学
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微生物学
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毒理学
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生物修复
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 24
·4639-4652
·
IF 6.583
Mengjing Zhao,Huan Zhao,Jiangming Deng,Lianxia Guo,Baojian Wu
Background and Purpose Whether and how circadian clock proteins regulate drug detoxification are not known. Here, we have assessed the effects of CLOCK (a core circadian clock protein) on drug metabolism and detoxification. Experimental Approach Regulation by CLOCK protein of drug-metabolizing enzymes was assessed using Clock knockout ( Clock −/− ) mice and Hepa-1c1c7/AML-12 cells. The relative mRNA and protein levels were determined by qPCR and Western blotting respectively. Toxicity and pharmacokinetic experiments were performed with Clock −/− and wild-type mice after intraperitoneal injection of coumarin or cyclophosphamide. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Key Results Clock deletion disrupted hepatic diurnal expressions of a number of drug-metabolizing enzymes in mice. In particular, CYP2A4/5 expressions were markedly down-regulated, whereas CYP2B10 was up-regulated. Positive regulation of Cyp2a4/5 and negative regulation of Cyp2b10 by CLOCK were confirmed in Hepa-1c1c7 and AML-12 cells. Based on a combination of luciferase reporter, mobility shift, and ChIP assays, we found that CLOCK activated Cyp2a4/5 transcription via specific binding to E-box elements in promoter region and repressed Cyp2b10 transcription through REV-ERBα/β (two target genes of CLOCK and transcriptional repressors of Cyp2b10 ). Furthermore, Clock ablation sensitized mice to coumarin toxicity by down-regulating CYP2A4/5-mediated metabolism (a detoxification pathway) and to cyclophosphamide toxicity by up-regulating CYP2B10-mediated metabolism (generating the toxic metabolite 4-hydroxycyclophosphamide). Conclusion and Implications CLOCK protein regulates metabolism by the cytochrome P450 family and drug detoxification. The findings improve our understanding of the crosstalk between circadian clock and drug detoxification.
研究领域:
药理学
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分子生物学
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昼夜节律
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高影响因子
FITOTERAPIA
·
2015
·
IF 2.345
Lili Wu,Wanping Zhong,Junjin Liu,Weichao Han,Shilong Zhong,Qiang Wei,Shuwen Liu,Lan Tang
Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China. This study aims to investigate the CYP450-mediated reduction responsible for metabolizing OSC and to evaluate the absorption and metabolism of OSC in rat in situ. Four metabolites were identified, with sophocarpine (SC) as the major metabolite. SC formation was rapid in human and rat liver microsomes (HLMs and RLMs, respectively). The reduction rates in the liver are two fold higher than in the intestine, both in humans and rats. In HLMs, inhibitors of CYP2C9 , 3A4/5, 2D6, and 2B6 had strong inhibitory effects on SC formation. Meanwhile, inhibitors of CYP3A and CYP2D6 had significant inhibition on SC formation in RLMs. Human recombinant CYP3A4/5, 2B6, 2D6, and 2C9 contributed significantly to SC production. The permeability in rat intestine and the excretion rates of metabolites were highest in the duodenum (p < 0.05), and the absorbed amount of OSC in duodenum and jejunum was concentration-dependent. The metabolism could be significantly decreased by CYP3A inhibitor ketoconazole. In conclusion, the liver was the main organ responsible for OSC metabolism. First-pass metabolism via CYP3A4/5, 2B6, 2D6, and 2C9 may be the main reason for the poor OSC bioavailability.
研究领域:
药理学
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毒理学
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中药学
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Wenwen Luo,Keqi Hu,Yijing Chen,Lin Wang,Yungang Liu
Tris(2-butoxyethyl) phosphate (TBOEP) is an organophosphorus flame retardant ubiquitously present in the environment and even the human body. TBOEP is toxic in multiple tissues, which forms dealkylated and hydroxylated metabolites under incubation with human hepatic microsomes; however, the impact of TBOEP metabolism on its toxicity, particularly mutagenicity (typically requiring metabolic activation), is left unidentified. In this study, the mutagenicity of TBOEP in human hepatoma cell lines (HepG2 and C3A) and the role of specific CYPs were studied. Through molecular docking, TBOEP bound to human CYP1A1, 1B1, 2B6 and 3A4 with energies and conformations favorable for catalyzing reactions, while the conformations of its binding with human CYP1A2 and 2E1 appeared unfavorable. In C3A cells (endogenous CYPs being substantial), TBOEP exposing for 72 h (2-cell cycle) at low micromolar levels induced micronucleus, which was abolished by 1-aminobenzotriazole (inhibitor of CYPs); in HepG2 cells (CYPs being insufficient) TBOEP did not induce micronucleus, whose effect was however potentiated by pretreating the cells with PCB126 (CYP1A1 inducer) or rifampicin (CYP3A4 inducer). TBOEP induced micronucleus in Chinese hamster V79-derived cell lines genetically engineered for stably expressing human CYP1A1 and 3A4, but not in cells expressing the other CYPs. In C3A cells, TBOEP selectively induced centromere protein B-free micronucleus (visualized by immunofluorescence) and PIG-A gene mutations, and elevated γ-H2AX rather than p-H3 (by Western blot) which indicated specific double-strand DNA breaks. Therefore, this study suggests that TBOEP may induce DNA/chromosome breaks and gene mutations in human cells, which requires metabolic activation by CYPs, primarily CYP1A1 and 3A4.
研究领域:
毒理学
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分子生物学
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细胞生物学
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PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2018
·
IF 4.358
Dandan Li,Peifang Wang,Chao Wang,Xiulei Fan,Xun Wang,Bin Hu
Organophosphate flame retardants (OPFRs), as alternatives to polybrominated biphenyl ethers (PBDEs), are frequently detected in various environmental matrices. Owing to urbanization and industrial pollution, co-contamination of OPFRs and heavy metals is ubiquitous in the environment. The toxicity of OPFRs in aqueous phase is a significant concern, but uncertainty still exists regarding the co-toxicity to benthic organisms of OPFRs and metals in sediments. Hence, we explored the physiological response of Corbicula fluminea to OPFRs and Cd in sediments. The results indicated that the antioxidant system in the clams was stimulated in the presence of OPFRs and Cd, and the oxidative stress increased with increasing concentrations of OPFRs. In contrast, the cytochrome P450 (CYP450) content and acetylcholinesterase (AChE) activity were reduced by exposure to both OPFRs and Cd. The cytochrome P450 4 family (CYP4) mRNA expression and OPFR toxicity were lower than those in previously reported experiments conducted in the water phase. Moreover, the expression levels of metallothionein (MT) and AChE mRNA decreased when OPFRs and Cd were present together. The highest integrated biomarker response (IBR) index (IBR = 15.41) was observed in the presence of 45 mg kg −1 Cd + 200 mg kg −1 OPFRs, rather than the 45 mg kg −1 Cd + 400 mg kg −1 OPFRs treatment (IBR = 9.48). In addition, CYP450 and AChE in the digestive glands of C. fluminea exhibited significant correlations with the concentration of the OPFR/Cd mixture (p < 0.01) and could be effective biomarkers for OPFR and Cd co-contamination. The results potentially contribute to more realistic predictions and evaluations of the environmental risks posed by OPFRs in aquatic sediments contaminated with heavy metals, particularly with respect to the risk to benthic organisms.
研究领域:
环境科学
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毒理学
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水生生态学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2019
·
IF 3.414
Bin Xie,Yuan-Yuan Lu,Zhuo-Hui Luo,Zhao Qu,Chun-Ge Zheng,Xin-An Huang,Hong-Yan Zhou,Ying-Jie Hu,Xiao-Ling Shen
Ethnopharmacological relevance Marsdenia tenacissima (Roxb.) Wight et Arn is a vine distributed in southwest area of China and used in folk medicine for treatment of tumors. Recent decades of studies on this plant reveal its synergistic effects with certain anticancer drugs in cancer therapy. In our previous study, an extract ETA which contains total aglycones made from M. tenacissima significantly enhanced antitumor activity of paclitaxel in tumor-bearing mice. However, the effective constituents in ETA and the underlying mechanisms remain unclear. Aim of the study Reveal the active components in ETA as well as the molecular mechanism in enhancing antitumor efficacy of paclitaxel. Material and methods Main constituents in ETA were purified by chemical methods. Effects of the purified constituents on metabolic activity of CYP450 enzymes were evaluated in human liver microsomes. Ability of the constituents to enhance antitumor activity of paclitaxel were investigated in nude mice bearing HeLa tumors. Pharmacokinetic study was performed in SD rats . Molecular docking was carried out for investigation of drug-protein interactions. Results Three main C 21 steroidal aglycones, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B ( MT1 ), 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B ( MT2 ) and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B ( MT3 ), together with tenacigenin B ( MT4 ) was prepared from ETA. Among them, MT1 , MT2 and MT3 strongly inhibit the metabolic activity of CYP3A4 . MT2 also showed inhibitory effects on CYP2C8 , CYP2B6 and CYP2C19 . In HeLa tumor xenografts, MT1 , MT2 and MT3 (30 mg/kg) did not affect tumor growth themselves, but significantly enhanced paclitaxel-induced growth inhibition. In addition, coadministration of MT2 with paclitaxel resulted in significant reduction of liver CYP2C8. In pharmacokinetic study, MT2 significantly increased the blood concentration of paclitaxel with increased AUC value by 2.2–5.3 folds. Molecular docking analysis suggested hydrophobic interaction modes of tenacigenin B derivatives with CYP3A4, and also the essential roles of the C-11 and C-12 ester groups for effective interaction with CYP3A4. Conclusion Our study proves that, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B, 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B, which are the main constituents of ETA, are active inhibitors of CYP3A4 with potential to increase therapeutic efficacy of anticancer drugs that are substrates of CYP3A4. Tenacigenin B derivatives with C-11 and C-12 ester group substitutions, or at least a large part of them, are active components in ETA and M. tenacissima to enhance in vivo antitumor efficacies of paclitaxel.
研究领域:
药理学
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肿瘤学
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民族药理学
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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
Journal of Proteomics
·
2019
·
IF 3.537
Zhuo-Qing Li,Ling-Li Wang,Jing Zhou,Xian Zheng,Yan Jiang,Ping Li,Hui-Jun Li
Dictamnine (DTN), a major furoquinoline alkoloid from Dictamni Cortex, was reported to induce hepatotoxicity. However, the underlying mechanism is unclear. In the present study, integrated transcriptomic and metabolomics analysis of mouse liver was performed in combination with serum biochemical and histopathological evaluation to investigate the potential mechanism. The results suggested that 640 mg/kg DTN significantly increased serum alanine transaminase and aspartate transaminase levels and induced serious cellular degeneration, with no changes occurring with 4 mg/kg DTN. Integrated analysis suggested that the metabolism of xenobiotics by cytochrome P450 , drug metabolism-other enzymes , bile secretion and glutathione metabolism were the major metabolic pathways involved in DTN-induced hepatotoxicity. Notably, 640 mg/kg DTN exposure increased hepatic GSH, GSH peroxidase , superoxide dismutase and malondialdehyde, and decreased ROS , together with altered expression of Idh2 and Nedd9. Representative genes, including Mup12 , Lipc, NTCP , MRP3, MRP4, CYP2E1 , CYP2D9 and UGT1A9 , in altered pathways were verified through PCR and Western blot . Collectively, the combined strategy of transcriptomics and metabolomics profiling could facilitate a better understanding for the discovery of metabolic pathways and that oxidative damage, ABC transporters and lipid metabolism might be the mechanisms linked to DTN-induced hepatotoxicity in mice. Significance Dictamnine (DTN) was reported to induce hepatotoxicity. Nevertheless, the underlying mechanism is unknown. This study is the first to utilize integrated transcriptomics and metabolomics in combination with general toxicity evaluation to characterize the potential molecular mechanism in DTN-induced hepatotoxicity in mice. We found that acute exposure to higher dose of DTN induced hepatocellular liver injury with more changes in biochemical parameters, genes and metabolites. Gene expression and metabolite profiles were more sensitive than general toxicity studies for detecting earlier hepatotoxicity. Integrated analysis suggested that oxidative damage, ABC transporters and lipid metabolism were closely correlated with DTN-induced hepatotoxicity. Overall, our results provide insights into the mechanism responsible for DTN-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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系统生物学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Ligui Wu,Hao Luo,Jingcheng Xu,Ling Yu,Jiangtao Xiong,Yizhi Liu,Xiangfeng Huang,Xiaoming Zou
The extensive use of antidiabetic drugs (ADDs) and their detection in high concentrations in the environment have been extensively documented. However, the mechanism of ADDs dissipation in aquatic environments is still not well understood. This study thoroughly investigates the dissipation behavior of ADDs and the underlying mechanisms in the aerobic activated sludge system. The results indicate that the removal efficiencies of ADDs range from 3.98% to 100% within 48 h, largely due to the biodegradation process. Additionally, the gene expression of cytochrome P450 (CYP450) is shown to be significantly upregulated in most ADDs-polluted samples (P < 0.05), indicating the vital role of CYP450 enzymes in the biodegradation of ADDs. Enzyme inhibition experiments validated this hypothesis. Moreover, molecular docking and simulation results indicate that a strong correlation between the biodegradation of ADDs and the interactions between ADDs and CYP450 (E binding ). The differences in dissipation behavior among the tested ADDs are possibly due to their electrophilic characteristics. Overall, this study makes the initial contribution to a more profound comprehension of the crucial function of CYP450 enzymes in the dissipation behavior of ADDs in a typical aquatic environment. Environmental Implication This work underscores the role of CYP450 enzymes in the biodegradation of antidiabetic drugs (ADDs). While removal efficiencies vary widely, the biodegradation process can lead to the formation of degradation products potentially more toxic than the original compounds. This points to a critical need for advanced wastewater treatment technologies capable of addressing not only the removal of ADDs but also the mitigation of their toxic byproducts. The study's findings emphasize the importance of understanding the specific mechanisms of pharmaceutical pollution, which is essential for protecting aquatic ecosystems and, by extension, human health from the unintended consequences of widespread pharmaceutical use.
研究领域:
环境科学
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生物技术
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药理学
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分子生物学
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PubMed
高影响因子
Natural Products and Bioprospecting
·
2024
·Vol. 14
·期 1
·1-21
·
IF 4.8
Lu Jindi,Liang Weimin,Hu Yiwei,Zhang Xi,Yu Ping,Cai Meiqun,Xie Danni,Zhou Qiong,Zhou Xuefeng,Liu Yonghong,Wang Junfeng,Guo Jiayin,Tang Lan
N -Hydroxyapiosporamide ( N -hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N -hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC–MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N -Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N -hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N -hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N -hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N -hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs. Graphical Abstract
研究领域:
药理学
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肿瘤学
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毒理学
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海洋生物学
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PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2021
·
IF 3.963
Jie Chen,Xin Hao,Buyong Wang,Ling Ma
Bursaphelenchus xylophilus is one of the most dangerous forest pathogens in the world, causing devastating pine forest deaths with considerable economic losses. In this study, we investigated the B. xylophilus RNA sequence responses of two different concentrations of levamisole hydrochloride (LH). We observed that body-wall muscle twitching, paralysis and, ultimately, death. 2.5 mg/ml and 3.5 mg/ml LH have toxicological effects on B. xylophilus , with mortality increasing significantly with concentration ( p < 0.05). RNA sequencing, differential gene expression analysis, and cluster analysis were performed, and 336, 384, 6 genes with significant variance in expression were identified. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the 12 intersecting genes revealed that these genes are mostly involved in metabolism of xenobiotics and have essential roles in drug sensitivity. Through the trend analysis of DEGs, it was divided into 8 modules, and the significant modules were selected to construct the co-expression network as the central genes of the drug metabolism-cytochrome P450 pathway (ko00982) and metabolism of xenobiotics by cytochrome P450 (ko00980). Eight highly related genes were identified, including cuticle collagen, cystathionine beta-synthase, endochitinase, pyruvate dehydrogenase E1 component subunit beta , aldehyde dehydrogenase , lipase , and zinc metalloproteinase . The expression levels of these genes were upregulated significantly at low concentrations and were significantly related to the resistance of B. xylophilus to LH. This study shows that B. xylophilus gene family expansions occurred in xenobiotic detoxification pathways through gene expression and potential horizontal correlated gene transfer with LH and helps to elucidate LH lethality and the evolutionary mechanisms underlying the adaptations of B. xylophilus to the environment. These results contributing to our understanding of B. xylophilus under LH and provide a data platform to providing a basis for its control.
研究领域:
分子生物学
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基因组学
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转录组学
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线虫学
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药物基因组学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）