Toxics
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2024
·Vol. 12
·期 2
·131
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IF 3.9
Qingxin Meng,Rong Huang,Shunhua Yang,Hui Li,Dan Yue,Xueyang Gong,Wenzheng Zhao,Yakai Tian,Kun Dong
Honey bees play a critical role as pollinators. However, their reproduction success and survival face severe threats due to the deterioration of their living environment. Notably, environmental conditions during their preimaginal stage inside brood cells can influence their immune capabilities and overall health after emergence. During the in-cell developmental stage, workers are in close contact with cocoons, which can become a source of stress due to accumulated metals. To investigate this potential threat, experiments were conducted to examine the impact of cocoons in brood cells used to rear different generations on the metal content and detoxification gene expression levels inApis cerana cerana. Our findings indicated significant differences in the layers, weight, base thickness, and metal contents like Cr, Cd, Pb, Mn, Ni, and As of cocoons in multi-generation brood cells compared to single-generation brood cells. These increases led to significant elevations in metal levels and upregulations of the four CYP450 detoxification genes in both six-day-old larvae and newly emerged workers. In conclusion, this study highlights the negative impact of cocoons in multi-generation brood cells on bee health and provides evidence supporting the development of rational apiculture management strategies for ecosystem stability.
研究领域:
昆虫学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2022
·
IF 3.571
Zhe Wang,Qing-qing Li,Cheng-ke Huang,Yan-yan Dong,Li-ping Lang,Wei Sun,Jian-chang Qian,Xiao-dan Zhang
In this study, we investigated the effect of type 1 diabetes mellitus on the modulation of the activities of CYP450s in dynamics by a UHPLC-MS/MS method. The diabetic rat model was constructed by an intraperitoneal single injection of streptozotocin . Fasting blood glucose levels > 16.7 mmol/L were considered as diabetic. The rats were given a cocktail of four probe drugs (10 mg/kg phenacetin , 1 mg/kg tolbutamide , 10 mg/kg metoprolol , and 10 mg/kg midazolam) by oral administration for the pharmacokinetic study. Thereafter, the metabolic ratio (MR) of the metabolites to probe substrates were determined. The results indicated that two weeks after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin (CYP1A2) and 4-hydroxyl tolbutamide/tolbutamide (CYP2C9); however, it decreased the MRs of α-hydroxy metoprolol/metoprolol (CYP2D6) and 1-hydroxy midazolam/midazolam (CYP3A4). Two months after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin and 4-hydroxyl tolbutamide/tolbutamide. The MR of α-hydroxy metoprolol/metoprolol was decreased and the MR of 1-hydroxy midazolam/midazolam was increased but the difference was not significant. According to the results, CYP1A2 and CYP2C9 activities were enhanced in the diabetic rats. and CYP2D6 activity was inhibited in a short period of diabetes; however, the decrease in CYP2D6 activity was not significant in the long period. CYP3A4 activity was decreased in a short period of diabetes and increased in a long period of diabetes but was not significant in the two periods. This study suggests the activity change rule of the CYP450 enzyme system in diabetes mellitus, which can provide a reference for precise clinical medication.
研究领域:
药理学
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代谢组学
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临床医学
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产品关联
DOI
PubMed
高影响因子
Infection and Drug Resistance
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2023
·
IF 3.9
Huaqiao Tang,Nana Long,Lin Lin,Yao Liu,Jianlong Li,Fenghui Sun,Lijuan Guo,Fen Zhang,Min Dai
Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a very damaging and widespread pathogen, which is associated with many diseases and causes serious infections. MRSA infection can modulate the effects of drugs, which may occur through an influence on cytochrome P450 (CYP450), the drug-metabolizing enzyme in the liver. In this study, we evaluated the underlying mechanism of drug failure or poisoning in MRSA infection.Materials and methods: Mice were infected with three different doses of MRSA and the changes in CYP450 expression, cytokines, and oxidative stress markers were evaluated.Results: The administration of an attack dose of MRSA caused serious symptoms of infection and resulted in a 40% mortality rate in the mice. MRSA induced strong inflammation and oxidative stress in the mice, predominantly caused by significant increases in interleukin (IL)-1β, IL-4, IL-6, macrophage inflammatory protein, glutathione S-transferase (GST), and malondialdehyde, and decreases in oxygen radical absorbance capacity and glutathione levels in the liver. The expression of IL-2, tumor necrosis factor-α, and GST was briefly suppressed, but increased on days 3 and 7. The increased inflammation and oxidative stress further induced a significant decrease in the mRNA levels and activities of CYP450 1A2, 2D22, 2E1, and 3A1 in MRSA-infected mice within the first day of infection.Conclusion: These results show that MRSA infection leads to inflammation and oxidative stress, and reduces the expression levels and activities of drug metabolism enzymes, which decreased drug metabolism in patients infected with MRSA. Therefore, to avoid a drug overdose, the plasma concentration of patients with MRSA infection should be continuously monitored.
研究领域:
医学
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药理学
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免疫学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2023
·Vol. 75
·期 3
·407-414
·
IF 3.3
Yin Xiaoting,Ma Suzhen,Li Mengyuan,Lu Shuaifei,Zhang Changjing,Liu Hui,Li Caiyin,Su Pan,Bai Ming,Li Yucheng
ObjectivesGefitinib is mainly used for the treatment of non-small-cell lung cancer. Hepatotoxicity is one of the main side effects of gefitinib, and seriously affects the treatment process of the disease. However, the hepatotoxicity mechanism of gefitinib remains unclear.MethodsThe hepatotoxicity of different doses of gefitinib was investigated in mice and AML-12 cells, and the possible correlation of hepatotoxicity with CYP450 was analysed.Key findingsThe toxic effects of gefitinib were confirmed by the increased liver index, decreased body weight and survival rate, injured liver function and histopathology followed 16 days of oral administration. Gefitinib (400 mg/kg) upregulated the hepatic mRNA expression of CYP1A1 and downregulated the CYP2D9 and CYP2D10 in mice. Furthermore, we verified that gefitinib produced cytotoxicity on AML-12 cells in a dose and time-dependent manner, and confirmed that gefitinib (20 μM) induced cell apoptosis, upregulated mRNA expression of CYP1A1 and downregulated CYP2D9 and CYP2D10. Pearson correlation analysis also showed that the hepatotoxicity of gefitinib was positively correlated with CYP1A1 and negatively correlated with CYP2D9 and CYP2D10.ConclusionsOur results suggested that the hepatotoxicity gefitinib may be associated with CYP1A1, CYP2D9 and CYP2D10. These findings will contribute to a better understanding of the mechanism of gefitinib 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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产品关联
DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2024
·
IF 4.9
Yingchang Song,Jiayu Zeng,Jianglan Long,Aiting Wang,Kuan Chen,Jia'an Qin,Dan Yan
Cytochrome P450 (CYP450) inhibition induced drug interactions (DDIs) are a primary cause of adverse drug reactions (ADRs). The rapid identification of CYP450 inhibitors is an important method for reducing potential ADRs. However, the existing methods are often intricate and time consuming, making them difficult to use for high-throughput rapid monitoring. Based on the specificity of CYP450 to the catalysis of different fluorescent substrate probes, an assay was developed to monitor the activity of six CYP450 isoforms simultaneously. The production rate of fluorescent metabolites characterized CYP450 activity. Method specificity was evaluated using inhibitors recommended by the FDA Guidelines for Drug Interaction Studies. We screened 28 clinically utilized medications for inhibition of CYP450 and evaluated the potential interaction by comparing inhibition constants ( K i ) and maximum plasma concentration (C max ). The analysis of the positive inhibitors using this method suggests that it allows for quick screening and identification of CYP450 inhibitors. Six drugs, including latoxefin, diclofenac, erythromycin lactate, labetalol, cimetidine, and droperidol, showed an interaction risk. The three isoforms of the CYP1A2, CYP3A4 and CYP3A5 metabolizing enzyme mediate a greater number of interactions, which should be specifically monitored in clinical applications. The established method permits rapid screening for inhibiting CYP1A2, CYP2E1, CYP2B6, CYP2A6, CYP3A4 and CYP3A5 with simple, stable, inexpensive, and high-throughput. This method will provide technical support for rapid discovery of clinical CYP450 inhibitors and risk avoidance of drug combination.
研究领域:
药理学
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分析化学
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药物发现
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临床药理学
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产品关联
DOI
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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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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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2022
·
IF 4.271
Shiqi Duan,Yan Jia,Zhihang Zhu,Lancheng Wang,Peng Xu,Youmei Wang,Bin Di,Chi Hu
Information regarding the metabolism of illicit drugs is under urgent need for toxicological assessment . Its development, however, is limited by the currently available animal models. To this end, we proposed three-dimensional (3D) HepaRG spheroids as an in vitro model to study the effects of illicit drugs on hepatic cytochrome P450 (CYP450) enzymes and potential drug-drug interactions (DDIs). By comparing the results from animal and cell experiments, we confirmed the significant impact of heroin, morphine, tetrahydrocannabinol , and fentanyl on CYP450 enzymes, and the 3D spheroids results were in good agreement with the animal results for 2B6, 2C19, 2D6. Using 3D HepaRG spheroids, we demonstrated DDIs between heroin as a 2B6 perpetrator and clinical medicine for cancer, depression, and illicit drug withdrawal. Specifically, the clearance rate of 5.4 μM bupropion was increased by 214 % under DDI with 5 µM heroin, highlighting the importance of DDI pre-screening and individualized medication guidance for illicit drug users. This research contributes to the growing body of evidence regarding the metabolic toxicity of illicit drugs and suggests 3D HepaRG spheroids as a high-throughput and cost-efficient platform for DDI analysis.
研究领域:
药理学
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毒理学
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细胞生物学
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药物代谢
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产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
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2020
·
IF 1.902
Yang Li,Jinjin Xu,Chunxia Xu,Zifei Qin,Shishi Li,Liufang Hu,Zhihong Yao,Frank J. Gonzalez,Xinsheng Yao
Corylifol A (CA), a phenolic compound from Psoralea corylifolia, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA.Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.Three oxidated metabolites (M1–M3) and two glucuronides (M4–M5) were detected. The intrinsic clearances (CLint) values of M1 and M4 in HLM were 48.10 and 184.03 μL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with CLint values of 13.01–49.36 μL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with CLint values ranging from 85.01 to 284.07 μL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells.Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics.
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
·
IF 3.4
Jinhua Li,Namrta Choudhry,Gang Lv,Naganna Nimishetti,Mallu Chenna Reddy,Hong Liu,Thaddeus D. Allen,Jing Zhang,Dun Yang
This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions , such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1 , and AO . Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC 50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development .
研究领域:
药理学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2018
·
IF 2.831
Chuqi Hou,Wenqin Liu,Zhi Liang,Weichao Han,Jinqing Li,Ling Ye,Menghua Liu,Zheng Cai,Jie Zhao,Yi Chen,Shuwen Liu,Lan Tang
Morusin is a prenylated flavone isolated from mulberry, the branch and root bark of various Morus species, which possesses diverse pharmacological activities. However, it lacks extensive studies about its absorption and disposition. This study investigated the pharmacokinetic behavior of morusin in rat, and its first-pass metabolism in situ . The metabolic pathway of morusin was further investigated by 12 human recombinant UDP-glucuronosyltransferases (UGTs), 9 CYP450s, as well as liver and intestinal microsomes. Four mono-glucuronide metabolites (M-5-G, M-4′-G, M-2′-G, and M II-2 ) were identified in rat intestine and bile by LC–MS/MS, while three of them were also detected in plasma (M-5-G, M-4′-G, and M II-2 ). M-4′-G was the principal conjugate. However, few CYP450 metabolites were found in rat intestine and bile. Only a small amount of M I-1 could be detected in rat plasma. UGT1A1, 1A3, 1A7, and 2B7 were the major contributors to morusin glucuronidation. Morusin exhibited substrate inhibition kinetic characteristics in all UGTs. Clearance rates of M-4′-G in HLM, RLM, UGT1A1, UGT1A3, and UGT2B7 were 137.02, 127.55, 32.54, 41.18, and 35.07 ml/min/mg, respectively. Besides, CYP3A5, 3A4, and 2C19 primarily contributed to the oxidative metabolism of morusin. The pharmacokinetic curves of morusin and its conjugates presented double peaks, showing that an enterohepatic recycling may exist. In conclusion, glucuronidation was confirmed to be the crucial metabolic pathway for morusin in vivo , and M-4′-G was the main metabolite.
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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DOI
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2022
·
IF 3.318
Xuan Guo,Lei Zhang,Zihan Lei,Zhe Hou,Hui Li,Xiaodong Li,Jing Dong,Ling Song,Dingding Chen,Dongyang Liu
Objective The aim of this study is to develop a LC-MS/MS method for the quantitation of seven cytochrome P450 (CYP450) enzymes. Methods A high-performance liquid chromatography-tandem mass spectrometry method was developed using multiple reaction monitoring mode with positive electrospray ionization. The method was validated with selectivity, linearity, stability, accuracy and precious. In addition, the abundance of seven CYP450 enzymes in human liver microsomes and CYP3A4 in placenta were determined using the current method. Results The linear range for CYP1A2, CYP2B6 and CYP2C8 was 0.036–3.6 nM and for CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was 0.090–9.0 nM. No interference was found between the blank matrix and each specific peptides. The accuracy and precious results were in accord with the requirement of analytical methods for biological samples in Chinese Pharmacopoeia. In addition, the peptides were stable under current stability conditions. The content of CYP3A4 in placenta and the seven CYP450 enzymes in human liver microsomes were accurately quantified. Conclusion The developed method is sensitive and specific and can be applied to the quantification of enzymes abundance in different human derived samples like placenta and liver microsomes.
研究领域:
药理学
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分析化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Lin Fei,Lin Xinhua,Wang Xuewen,Mei Guanghui,Chen Bing,Yao Hong,Huang Lingyi
Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS.Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms.Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC50 ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC50 < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC50 < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes.Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.
研究领域:
药理学
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中药学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）