CURRENT DRUG METABOLISM
·
2024
·Vol. 25
·期 8
·586-604
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IF 2.1
Jiang Pu,Wanyong Feng
BackgroundFerrets exhibit similar lung physiology to humans and display similar clinical signs following influenza infection, making them a valuable model for studying high susceptibility and infection patterns. However, the metabolic fate of several common human CYP450 probe substrates in ferrets is still unknown and has not been studied.ObjectiveThe purpose of this study was to investigate the metabolism of nine human CYP450 probe substrates in ferret hepatocytes and explore their metabolic rate differences between ferrets and other species.MethodsNine substrates were individually incubated in ferret hepatocytes for up to 120 min. At each time point, 30 µL mixtures were extracted for stability analysis using LC-MS/MS methods. After a 120-minute incubation period, 400 µL of the mixtures were extracted for metabolite identification using UHPLC-Q-Exactive Plus.ResultsThe metabolic clearance was determined as follows: testosterone > phenacetin > bupropion > omeprazole > midazolam > dextromethorphan > chlorzoxazone > taxol > diclofenac. Seven metabolites were identified from phenacetin. Deethylation was found to be the major pathway, and the major metabolite was matched with acetaminophen as probed with the CYP1A2 enzyme. Six metabolites were identified from diclofenac. Glucuronidation was the primary pathway, and a metabolite was found to match 4-OH-diclofenac as probed with the CYP2C9 enzyme. Twenty-two metabolites were identified from omeprazole. The major metabolic pathways included mono-oxygenation and sulfoxide to thioether conversion. No metabolite was found to match with 5-OH-omeprazole as probed with the CYP2C19 enzyme. Twenty-two metabolites were identified from dextromethorphan. Demethylation was found to be the major metabolic pathway, and one demethylation metabolite was matched with dextrorphan as probed with the CYP2D6 enzyme. Fourteen metabolites were identified from midazolam. Mono-oxygenation was found to be the primary metabolic pathway, and one of the mono-oxygenation metabolites was matched with 1-OH-midazolam as probed with the CYP3A4 enzyme. Eight metabolites were identified from testosterone. Mono-oxygenation and glucuronidation were identified as the major metabolic pathways. One mono-oxygenation was matched with 6-β-testosterone as probed with the CYP3A4 enzyme. Six metabolites were identified from taxol. Hydrolysis and mono-oxygenation were the top two metabolic pathways. No metabolite was matched with 6-α-OH-taxol as probed with the CYP2C8 enzyme. Ten metabolites were identified from bupropion. Mono-oxygenation and hydrogenation were identified as the top two metabolic pathways. No mono-oxygenation metabolite was matched with hydroxy-bupropion as probed with the CYP2B6 enzyme. Nine metabolites were identified from chlorzoxazone. Mono-oxygenation and sulfation were the top two metabolic pathways. One mono-oxygenation metabolite was matched with 6-OH-chlorzoxazone as probed with the CYP2E1 enzyme.ConclusionNine human CYP probe substrates were clearly metabolized in ferret hepatocytes, demonstrating substrate-dependent metabolic rates in ferret hepatocytes and species-dependent metabolic rates in mouse, rat, dog, monkey, and human hepatocytes. Except for 6-a-5-OH-omeprazole, 6-α-OH-taxol, and hydroxy-bupropion, specific metabolites of other six probe substrates in ferret hepatocytes were detected and identified as probed with six human CYP enzymes, respectively.
研究领域:
药理学
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生物化学
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高影响因子
npj Science of Food
·
2024
·Vol. 8
·期 1
·1-12
·
IF 6.3
Zhang Meng,Du Pengfei,Xiao Yirong,Liu Hao,Wang Meixue,Zhang Yumei,Chen Xin
Sodium dehydroacetate (DHA-Na), a widely used preservative, can induce sex-differentiated coagulation disorders primarily resulting from its metabolism. However, the underlying mechanisms remain poorly understood. Here, we identified several Cytochrome P450 (CYP450) sub-enzymes involved in sex differences related to DHA-Na metabolism, along with two related DHA-Na metabolites. CYP1A2, CYP3A2, and CYP2D1 were primarily responsible for DHA-Na metabolism, which was stronger in male rats than in female rats. Inhibition of these isoforms separately resulted in the DHA-Na metabolic capacity in male rats becoming equal to, or even weaker than, that in female rats. Furthermore, Cyp1a2, Cyp3a2, Cyp2d1 , and Cyp2c11 expression was higher in male rats than in female rats, suggesting these enzymes are related to exhibited sex differences in DHA-Na metabolism. Moreover, 3-glycoloyl-6-methy-2,3-dihydropyran-2,4-dione (C 8 H 8 O 5 ) and 3-imino-6-methyl-2,3-dihydropran-2,4dione (C 6 H 5 O 3 N) were identified as the two main DHA-Na metabolites. These findings provide crucial insights into potential mechanisms underlying sex differences in DHA-Na metabolism and its metabolites in rats.
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
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Ziming Zheng,Yu Zhang,Yuxuan Liu,Jinglin Wang,Zheng Cui,Xianglin Pan,Yan Liu,Wenqi Tang,Kaiping Wang
Lentinan (LNT), a typical triple helix β-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other β-glucans.
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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高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2022
·Vol. 130
·期 5
·592-605
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IF 3.688
Zhiping Jin,Qingfeng He,Xiao Zhu,Mingshe Zhu,Yike Wang,Xin-an Wu,Qianzhou Lv,Xiaoqiang Xiang
Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non-small cell lung cancer in China. Drug–drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co-administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens.
研究领域:
药理学
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临床药学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2017
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IF 3.743
Wei Xie,Fangxing Yang
Although enantioselective accumulation of chiral pesticide has been reported in organisms, the mechanisms remain unclear. In this study, the effects of chiral pesticide metalaxyl on CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP2E1 and CYP3A were investigated in human hepatoma HepG2, rat hepatic H4IIE, chicken hepatic LMH and grass carp hepatic L8824 cells. Moreover, the residual concentrations and enantiomeric ratios (ERs) of metalaxyl were also detected in the medium. The results showed the responses of these CYP450s to metalaxyl were enzyme-dependent and species-dependent in the four cells. CYP1A1, CYP1A2, and CYP2B1 were induced in HepG2 cells, CYP2A1 and CYP2B1 were induced in H4IIE cells, CYP1A1 and CYP2B1 were induced in LMH cells, and CYP2B1 was induced in L8824 cells. The enantioselective residual of metalaxyl was detected in the medium and found to be species-specific. HepG2, H4IIE and LMH cells were inclined to attenuate S -metalaxyl and lead to decrease of ER of metalaxyl, while L8824 cells were inclined to remove R -metalaxyl and resulted in an inverse shift of ER. These findings suggest an enantioselective metabolism of metalaxyl in various species which is not only related with CYP450s and CYP450 enzyme-specific, but also species-specific.
研究领域:
环境科学
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毒理学
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药理学
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PubMed
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Chinese Journal of Natural Medicines
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2019
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IF 1.773
Yu-Xin WANG,Yi DU,Xia-Fei LIU,Fang-Xiu YANG,Xiao WU,Li TAN,Yi-Hong LU,Jing-Wei ZHANG,Fang ZHOU,Guang-Ji WANG
ABSTRACT We investigated the potential hepatoprotective effect of Radix Bupleuri (RB) by inducing acute liver injury (ALI) in an animal model using acetaminophen (APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serumaspartate transaminase (AST) and alanine transaminase (ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine (APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione (GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2E1 and CYP3A activity. Further investigation revealed the increasing of CYP2E1 and CYP3A protein was significantly inhibited in pretreatment group, while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.
研究领域:
药理学
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毒理学
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肝脏研究
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TOXICOLOGY IN VITRO
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2023
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IF 3.2
Ni-hong Pang,Ren-ai Xu,Lian-guo Chen,Zhe Chen,Guo-xin Hu,Bo-wen Zhang
Purpose The inhibitory effect of Apatinib on cytochrome P450 (CYP450) enzymes has been studied. However, it is unknown whether the inhibition is related to the major metabolites, M1–1, M1–2 and M1–6. Methods A 5-in-1 cocktail system composed of CYP2B6/Cyp2b1, CYP2C9/Cyp2c11, CYP2E1/Cyp2e1, CYP2D6/Cyp2d1 and CYP3A/Cyp3a2 was used in this study. Firstly, the effects of APA and its main metabolites on the activities of HLMs, RLMs and recombinant isoforms were examined. The reaction mixture included HLMs, RLMs or recombinant isoforms (CYP3A4.1, CYP2D6 .1, CYP2D6.10 or CYP2C9 .1), analyte (APA, M1–1, M1–2 or M1–6), probe substrates. The reactions were pre-incubated for 5 min at 37 °C, followed by the addition of NAPDH to initiate the reactions, which continued for 40 min. Secondly, IC 50 experiments were conducted to determine if the inhibitions were reversible. The reaction mixture of the “+ NADPH Group” included HLMs or RLMs, 0 to 100 of μM M1–1 or M1–2, probe substrates. The reactions were pre-incubated for 5 min at 37 °C, and then NAPDH was added to initiate reactions, which proceeded for 40 min. The reaction mixture of the “– NADPH Group” included HLMs or RLMs, probe substrates, NAPDH. The reactions were pre-incubated for 30 min at 37 °C, and then 0 to 100 μM of M1–1 or M1–2 was added to initiate the reactions, which proceeded for 40 min. Finally, the reversible inhibition of M1–1 and M1–2 on isozymes was determined. The reaction mixture included HLMs or RLMs, 0 to 10 μM of M1–1 or M1–2, probe substrates with concentrations ranging from 0.25 K m to 2 K m . Results Under the influence of M1–6, the activity of CYP2B6 , 2C9, 2E1 and 3A4/5 was increased to 193.92%, 210.82%, 235.67% and 380.12% respectively; the activity of CYP2D6 was reduced to 92.61%. The inhibitory effects of M1–1 on CYP3A4/5 in HLMs and on Cyp2d1 in RLMs, as well as the effect of M1–2 on CYP3A in HLMs, were determined to be noncompetitive inhibition, with the K i values equal to 1.340 μM, 1.151 μM and 1.829 μM, respectively. The inhibitory effect of M1–1 on CYP2B6 and CYP2D6 in HLMs, as well as the effect of M1–2 on CYP2C9 and CYP2D6 in HLMs, were determined to be competitive inhibition, with the K i values equal to 12.280 μM, 2.046 μM, 0.560 μM and 4.377 μM, respectively. The inhibitory effects of M1–1 on CYP2C9 in HLMs and M1–2 on Cyp2d1 in RLMs were determined to be mixed-type, with the K i values equal to 0.998 μM and 0.884 μM. The parameters could not be obtained due to the atypical kinetics of CYP2E1 in HLMs under the impact of M1–2. Conclusions M1–1 and M1–2 exhibited inhibition for several CYP450 isozymes , especially CYP2B6, 2C9, 2D6 and 3A4/5. This observation may uncover potential drug-drug interactions and provide valuable insights for the clinical application of APA.
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Agronomy-Basel
·
2026
·Vol. 16
·期 13
·1271
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IF 4.1
Qian Qiu,Zhiwu Huang,Aisheng Xiong,Guofei Tan,Sucheng Ren,Daguo Gu,Hengyu Meng,Luzhao Pan,Weimin Zhu,Jun Yan
The Cytochrome P450 (CYP) superfamily plays an important role in the regulation of plant growth and development. However, the composition, evolutionary characteristics, and potential functions of CYPs in celery remain largely unexplored. Therefore, the objective of this study was to perform a genome-wide characterization of theApium graveolensCytochrome P450 (AgCYP) gene family and investigate its potential roles in seed development. In this study, a total of 227AgCYPswere identified, and phylogenetic analysis classified them into six clades. Conserved motif and domain evaluations indicated that most AgCYP proteins possess conserved P450 domains. Chromosomal localization revealed an unequal distribution ofAgCYPsacross the 11 celery chromosomes. DuplicatedAgCYPgene pairs were identified by synteny and Ka/Ks analyses, indicating that the duplicatedAgCYPshave undergone strong purifying selection. Inter-genomic synteny analysis further reflects the closer relationship within Apiaceae. Analysis ofcis-acting elements in the promoter regions identified an abundance of elements associated with light, hormone, and environmental stress. Moreover,AgCYPsshowed stage-specific expression patterns and were correlated with monoterpene and phthalide accumulation during celery seed development, suggesting their potential functions in secondary metabolism in seed development. Treatment with exogenous auxin and its transport and biosynthesis inhibitors differentially induced distinct expression responses amongAgCYPs, indicating their possible participation in auxin-related regulatory pathways. Moreover, candidate genes were selected. They exhibited diverse tissue-specific expression patterns and were potentially localized to the endoplasmic reticulum and interacted with some auxin-related proteins. In conclusion, this study provides the first comprehensive framework for understanding the functional diversification of AgCYPs in celery seeds, providing new insights into the evolutionary features and biological functions of theAgCYPgene family and establishing a foundation for future functional studies and molecular breeding applications.
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RESEARCH IN VETERINARY SCIENCE
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2023
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IF 2.4
Dongliu Luo,Yiming Lu,Qiaohan Liu,Hang Yin,Xiaodan Huang,Shu Li
Cadmium (Cd) is toxic non-essential heavy metal that precipitates adverse health effects in humans and animals, but the effect of Cd on lymph node toxicity of piglets is still unclear. In order to explore the possible molecular mechanism of Cd toxicity to lymph nodes of piglets, ten 6-week-old male weaned piglets were randomly divided into two groups, C group and Cd group. Group C was fed with basal diet, while group Cd was fed with basal diet supplemented with CdCl 2 (20 mg/kg) for 40 days, the pigs were euthanized and the mesenteric, inguinal and submandibular lymph nodes (MLN, ILN, SLN) were collected. The results indicated that Cd could induce the inflammatory cell infiltration , microvascular hemorrhage, microthrombosis and cell necrosis in MLN, ILN and SLN of piglets, induced Cytochrome P450 proteins (CYP1A1、CYP2E1、CYP2A1 and CYP3A2) mRNA levels and the protein levels of Vitamin D receptor (VDR) and cAMP response element binding protein 1 (CREB1). In addition, Cd exposure upregulated the mRNA and protein levels of dynamin-related protein 1 (DRP1), receptor-interacting protein kinase 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), and increased tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), interleukin-2 (IL-2), interleukin-4 (IL-4), cyclooxygenase 2 (COX-2) protein levels, and the damage degree of three kinds of lymph nodes was similar after Cd exposure. In general, these results manifest that Cd exposure regulates VDR/CREB1 pathway, activates CYP450s , induces necroptosis of lymph nodes, and leads to inflammation.
研究领域:
毒理学
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免疫学
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分子生物学
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动物科学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2015
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IF 2.998
Ting Geng,Haihong Si,Danyu Kang,Yanjing Li,Wenzhe Huang,Gang Ding,Zhenzhong Wang,Yu’an Bi,Hong Zhang,Wei Xiao
Ethnopharmacological relevance Re Du Ning Injection (RDN), a traditional Chinese medicine injection, is made from the extracts of Lonicerae japonicae flos (LJF), Artemisiae annuae herba (AAH) and Gardeniae fructus (GF). Since last decade, RDN has been widely used in China for the treatment of fever, inflammation, allergy and viral infection. Aim of the study To elucidate the potential influences of RDN on the activities of four cytochrome P450 (CYP) isozymes in rats (CYP1A2, CYP2C11 , CYP2D1 and CYP3A1/2) by “cocktail method”. Materials and methods A sensitive and specific LC–MS method capable of simultaneous quantification of four substrates and their metabolites in rat plasma was developed and validated. Relative activity estimation of four isozymes was carried out by comparing plasma pharmacokinetics of substrates and their metabolites (phenacetin/ paracetamol for CYP1A2 , tolbutamide/4-hydroxytolbutamide for CYP2C11, dextromethorphan/ dextrorphan for CYP2D1 and dapsone/N-acetyl dapsone for CYP3A1/2) between control and RDN treatment groups. Results Compared with control group, RDN at different levels could increase the total amount of tolbutamide , dextromethorphan and dapsone absorbed into blood, while decrease the total amount of phenacetin absorbed into blood at low and medium dosage and increase it at high dosage. Conclusions RDN could inhibit the activities of CYP2C11, CYP2D1 and CYP3A1/2, induce the activity of CYP1A2 at low and medium dosage but inhibit it at high dosage. The results indicated that drug co-administrated with RDN may need dose adjustment.
研究领域:
药理学
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中药学
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临床医学
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PubMed
高影响因子
Environmental Sciences Europe
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2019
·Vol. 31
·期 1
·1-14
·
IF 5.878
Tang Huaqiao,Xu Min,Luo Jie,Zhao Ling,Ye Gang,Shi Fei,Lv Cheng,Chen Helin,Wang Yanyan,Li Yinglun
The widespread use of nano-copper as a feed additive in the absence of toxicological studies has potential risks to humans and animals. Toxicity studies on nano-copper in animals usually exposure from the respiratory tract, however, it is necessary to study the oral exposure toxicity of nano-copper to understand its risks as a feed additive.Currently the hepatotoxicity and mechanism of nano-copper after sub-choronic oral exposure at equivalent doses of 50, 100, and 200 mg/kg/day were evaluated in rats; micro-copper and Cu ions were used as controls. Nano-copper (200 mg/kg) increased serum alanine aminotransferase and aspartate aminotransferase significantly, further promoting hepatic oxidative stress, inflammation, and corresponding histopathological changes, and exhibited significant dose-dependent changes. Nano-copper also decreased the level of nuclear receptors, resulting in significant reductions in mRNA, protein, and activity of hepatic CYP450 enzymes. The molecular mechanisms responsible for these toxic effects involved the signaling pathway of NF-κB, MAPK, and STAT5.Nano-copper caused strong hepatic toxicity by inducing oxidative stress and inflammation. The decreased drug metabolism enzymes lead to nano-copper–drug interaction that provoked the concerns on animal-derived food safety.
研究领域:
毒理学
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药理学
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兽医学
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环境健康
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高影响因子
Chemical Biology & Drug Design
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2023
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IF 3
Jie Li,Xiuheng Liu
This work is performed to investigate the effect of coptisine (COP) on the malignant biological behaviors of bladder carcinoma cells and its underlying mechanism. Bladder carcinoma cell lines were treated with different concentrations of COP in vitro. Cell counting kit-8 (CCK-8), scratch healing assay, Transwell assay, and flow cytometry were used to detect cell growth, migration, invasion, and cell cycle progression. Bioinformatics analysis was performed to predict the molecular targets of COP. Quantitative real-time PCR and western blot were adopted to determine the expression levels of exportin 1 (XPO1) mRNA and protein, respectively. Gene set enrichment analysis was applied to predict the signaling pathways related to XPO1. This study showed that COP treatment markedly suppressed the malignant biological behaviors of bladder carcinoma cells. XPO1 was identified as a downstream molecular target of COP in bladder carcinoma, and COP treatment inhibited the expression of XPO1 in bladder carcinoma cell lines. Overexpression of XPO1 reversed the impacts of COP on the malignant biological behaviors of bladder carcinoma cells. COP treatment modulated the expression level of cyclin D1 and CYP450 via XPO1. In summary, COP represses the malignant biological behaviors of bladder carcinoma cells and regulates XPO1 expression, which is promising to be a complementary drug for bladder carcinoma treatment.
研究领域:
肿瘤学
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药理学
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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
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