JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Mingtao Tan,Hong Jiang,Rusong Chai,Miao Fan,Zengting Niu,Guotong Sun,Shanchun Yan,Dun Jiang
Heavy metal pollutants are important abiotic environmental factors affecting pest habitats. In this study, Cd pre-exposure significantly increased the tolerance of Lymantria dispar larvae to β-cypermethrin, but did not significantly alter their tolerance to λ-cyhalothrin and bifenthrin. The activation of P450 by Cd exposure is the key mechanism that induces insecticide cross-tolerance in L. dispar larvae. Both before and after β-cypermethrin treatment, Cd exposure significantly increased the expression of CYP6AB224 and CYP6AB226 in L. dispar larvae. Silencing CYP6AB224 and CYP6AB226 reduced the tolerance of Cd-treated L. dispar larvae to β-cypermethrin. Transgenic CYP6AB224 and CYP6AB226 genes significantly increased the tolerance of Drosophila and Sf 9 cells to β-cypermethrin, and the recombinant proteins of both genes could significantly metabolise β-cypermethrin. Cd exposure significantly increased the expression of CnCC and Maf . CnCC was found to be a key transcription factor regulating CYP6AB224 - and CYP6AB226 -activated insecticide cross-tolerance in Cd-treated larvae. Decreasing reactive oxygen species (ROS) levels in the Cd-treated larvae or increasing ROS levels in the untreated larvae reduced or enhanced the expression of CnCC , CYP6AB224 and CYP6AB226 and β-cypermethrin tolerance in L. dispar larvae, respectively. Collectively, Cd exposure confers β-cypermethrin tolerance in L. dispar larvae through the ROS/ CnCC signalling pathway-mediated P450 detoxification. Environmental Implication Heavy metals have been reported to produce cross-tolerance in agricultural insects to insecticides. The growing demand for chemical pest control necessitates expanding research on the widespread occurrence of cross-tolerance to insecticides among pests, particularly forest pests, in areas polluted with heavy metals. In this study, Cd pre-exposure enhanced the cross-tolerance of Lymantria dispar larvae to β-cypermethrin. Cd pre-exposure activated the P450 detoxification system of L. dispar larvae. CYP6AB224 and CYP6AB226 were key detoxify genes to the formation of cross-tolerance. ROS-CnCC signaling pathway was proved to be responsible for activation of detoxify genes.
研究领域:
环境科学
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昆虫学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
AAPS Journal
·
2016
·Vol. 19
·期 1
·203-214
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IF 3.819
Zhong Shilong,Han Weichao,Hou Chuqi,Liu Junjin,Wu Lili,Liu Menghua,Liang Zhi,Lin Haoming,Zhou Lili,Liu Shuwen,Tang Lan
Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles ( n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the Grey sWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.
研究领域:
药理学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
Gut Pathogens
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2023
·Vol. 15
·期 1
·1-14
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IF 4.2
Wang Shanshan,Wen Qiuyu,Qin Yan,Xia Quan,Shen Chenlin,Song Shuai
Background The pseudo germ-free (PGF) model has been widely used to research the role of intestinal microbiota in drug metabolism and efficacy, while the modelling methods and the utilization of the PGF model are still not standardized and unified. A comprehensive and systematic research of the PGF model on the composition and function of the intestinal microbiota, changes in host cytochrome P450 (CYP450) enzymes expression and intestinal mucosal permeability in four different modelling cycles of the PGF groups are provided in this paper.Results 16S rRNA gene amplicon sequencing was employed to compare and analyze the alpha and beta diversity, taxonomic composition, taxonomic indicators and predicted function of gut microbiota in the control and PGF groups. Bacterial richness and diversity decreased significantly in the PGF group beginning after the first week of establishment of the PGF model with antibiotic exposure. The PGF group exposed to antibiotics for 4-week-modelling possessed the fewest indicator genera. Moreover, increased intestinal mucosal permeability occurred in the second week of PGF model establishment, indicating that one week of antibiotic exposure is an appropriate time to establish the PGF model. The results of immunoblots revealed that CYP1A2, CYP2C19 and CYP2E1 expression was significantly upregulated in the PGF group compared with the control group, implying that the metabolic clearance of related drugs would change accordingly. The abundance of functional pathways predicted in the gut microbiota changed dramatically between the control and PGF groups.Conclusion sThis study provides information concerning the microbial and CYP450 enzyme expression profiles as a reference for evaluating drug metabolism differences co-affected by gut microbiota and host CYP450 enzymes in the PGF model.
研究领域:
药理学
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微生物学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Li Yingzi,Liu Xiaoyan,Li Ludi,Zhang Tao,Gao Yadong,Zeng Kewu,Wang Qi
Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.
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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产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
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2021
·
IF 1.908
Yun-Jing Zhang,Wen-Li Zhou,Fei Yu,Qian Wang,Can Peng,Jia-Yi Kan
Bovis Calculus Artifactus (BCA) is the main substitute for natural Calculus bovis, a traditional drug in China used to treat high fever, convulsion, and sore throat. The effect of BCA on cytochrome P450 (CYP) activities is unknown. This study was to investigate the effect of BCA on eight rat hepatic microsomal CYPisozymes to evaluate the potential drug interactions using the cocktail approach.Metabolites of the eight isoform probe substrates of CYP isozymes were quantified by LC-MS/MS. The method was validated by incubating known CYP inhibitors α-naphthoflavone (CYP1A2), thiotepa (CYP2B1), quercetin (CYP2C7), sulfaphenazole (CYP2C6), ticlopidine (CYP2C11), quinidine (CYP2D1), ketoconazole (CYP3A1),4-methylpyrazole (CYP2E1) with individual probe substrate and rat liver microsomes. The formation rates of the corresponding metabolites of the eight probe substrates were determined to evaluate the activity of each isozyme.The results showed that BCA has different degrees of inhibitory effect on four CYP450 isoforms (CYP2C6, CYP2C11, CYP2D1, CYP3A1) (p < 0.05), but no significant influence on CYP1A2, 2B1, 2C7 or 2E1 (p > 0.05). Attention should be paid to the BCA-drug interactions by careful monitoring and appropriate dosage adjustments in the concurrent use of the drugs which are metabolized by CYP1A2, CYP2C19, and CYP3A4. Abbreviations: BCA, bovis calculus artifactus; CYP, cytochrome P450; DDIs, drug-drug interactions; ESI, electrospray ionization; MRM, multiple reaction monitoring; NBC, Natural Bovis Calculus; QC, quality control; T CM, traditional Chinese medicine.
研究领域:
药理学
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药物代谢
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中医药
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产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2023
·
IF 8.8
Wei Jia,Xin Wang
Endogenous aflatoxin B1 (AFB1) was quantified in five hundred and forty Hengshan goat meat samples (0.00 ± 23.09 μg kg −1 ). Zanthoxylum bungeanum ( Z. bungeanum ), as a natural pickling spice, can ameliorate the flavor of animal-derived food (goat meat). Yet, considering the direct administration of Z. bungeanum in AFB1-contaminated goat meat, the degradation mechanisms of AFB1 remain elusive. Here, UHPLC-Q-Orbitrap HRMS-based integrative metabolomics (LOQ: 1.74–59.54 μg kg −1 ) and proteomics analyses were executed to determine the effects of Z. bungeanum in the biotransformation of AFB1. Z. bungeanum (1.50 %, w/w ) application mediated the metabolism of xenobiotics by cytochrome P450, significantly down-regulated cytochrome P450 1A and stimulated the up-regulation of glutathione S-transferase levels in AFB1-contaminated goat meat, leading to degradation of AFB1 (20.00–3.39 μg kg −1 ). Metabolomics assays indicated that Z. bungeanum up-regulated l -histidine (1.43–2.21 mg kg −1 ) and l -arginine, manifesting potential applications for the contribution of Z. bungeanum to the nutritional value of goat meat.
研究领域:
食品安全
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毒理学
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代谢组学
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蛋白质组学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2024
·
IF 10.8
Zehua Song,Xiaomei Yu,Minghua Zhu,Zimeng Wu,Zhiqiang Fu,Jingwen Chen
The tire rubber antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its quinone product (6PPDQ) are prevalent emerging contaminants, yet their biotransformation profiles remain poorly understood, hampering the assessment of environmental and health risks. This study investigated the phase-I metabolism of 6PPD and 6PPDQ across aquatic and mammalian species through in vitro liver microsome (LM) incubations and in silico simulations. A total of 40 metabolites from seven pathways were identified using the highly sensitive nano-electrospray ionization mass spectrometry. Notably, 6PPDQ was consistently detected as a 6PPD metabolite with an approximate 2% yield, highlighting biotransformation as a neglected indirect exposure pathway for 6PPDQ in organisms. 6PPDQ was calculated to form through a facile two-step phenyl hydroxylation of 6PPD, catalyzed by cytochrome P450 enzymes. Distinct species-specific metabolic kinetics were observed, with fish LM demonstrating retarded biotransformation rates for 6PPD and 6PPDQ compared to mammalian LM, suggesting the vulnerability of aquatic vertebrates to these contaminants. Intriguingly, two novel coupled metabolites were identified for 6PPD, which were predicted to exhibit elevated toxicity compared to 6PPDQ and result from C–N oxidative coupling by P450s. These unveiled metabolic profiles offer valuable insights for the risk assessment of 6PPD and 6PPDQ, which may inform future studies and regulatory actions.
研究领域:
环境科学
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毒理学
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生物化学
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药理学
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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
Jinjin Xu,Mengsen Li,Zhihong Yao,Yezi Zhang,Shishi Li,Liufang Hu,Zifei Qin,Frank J. Gonzalez,Xinsheng Yao
Neobavaisoflavone (NBIF), a phenolic compound isolated from Psoralea corylifolia L., possesses several significant biological properties. However, the pharmacokinetic behaviors of NBIF have been characterized as rapid oral absorption, high clearance, and poor oral bioavailability. We found that NBIF underwent massive glucuronidation and oxidation by human liver microsomes (HLM) in this study with the intrinsic clearance ( CL int ) values of 12.43, 10.04, 2.01, and 6.99 μL/min/mg for M2, M3, M4, and M5, respectively. Additionally, the CL int values of G1 and G2 by HLM were 271.90 and 651.38 μL/min/mg, respectively, whereas their respective parameters were 59.96 and 949.01 μL/min/mg by human intestine microsomes (HIM). Reaction phenotyping results indicated that CYP1A1, 1A2, 2C8, and 2C19 were the main contributors to M4 (34.96 μL/min/mg), M3 (29.45 μL/min/mg), M3 (13.16 μL/min/mg), and M2 (63.42 μL/min/mg), respectively. UGT1A1, 1A7, 1A8, and 1A9 mainly catalyzed the formation of G1 (250.87 μL/min/mg), G2 (438.15 μL/min/mg), G1 (92.68 μL/min/mg), and G2 (1073.25 μL/min/mg), respectively. Activity correlation analysis assays showed that phenacetin- N -deacetylation was strongly correlated to M3 ( r = 0.860, p = 0.003) and M4 ( r = 0.775, p = 0.014) in nine individual HLMs, while significant activity correlations were detected between paclitaxel-6-hydroxylation and M2 ( r = 0.675, p = 0.046) and M3 ( r = 0.829, p = 0.006). There was a strong correlation between β-estradiol-3- O -glucuronide and G1 ( r = 0.822, p = 0.007) and G2 ( r = 0.689, p = 0.040), as well as between propofol- O -glucuronidation and G1 ( r = 0.768, p = 0.016) and G2 ( r = 0.860, p = 0.003). Moreover, the phase I metabolism and glucuronidation of NBIF revealed marked species differences, and mice are the best animal model for investigating the metabolism of NBIF in humans. Taken together, characterization of NBIF-related metabolic pathways involving in CYP1A1, 1A2, 2C8, 2C19, and UGT1A1, 1A7, 1A8, 1A9 are helpful for understanding the pharmacokinetic behaviors and conducting in-depth pharmacological studies.
研究领域:
药物代谢
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生物化学
·
药理学
✓ 已验证
DOI
高影响因子
ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY
·
2021
·Vol. 41
·期 1
·230-239
·
IF 3.742
Siqi Wu,Huizhen Li,Jing You
Fipronil has been frequently detected in waterways worldwide at concentrations that threaten aquatic organisms, yet the metabolic behavior of fipronil enantiomers in aquatic organisms is largely unknown, which is of significance in enantioselective toxicity evaluation. We quantitatively identified the specific cytochrome P450 (CYP) isozymes involved in metabolizing fipronil enantiomers in tilapia by combining in vitro metabolic kinetic assays and molecular docking. Inhibition studies suggested that CYP1A enzyme was the main isoform catalyzing metabolism of fipronil and that CYP3A contributed in a limited way to the metabolism in fish liver S9. Both the dissipation rate constant and the maximum metabolic velocity of R -(−)-fipronil were greater than those of S -(+)-fipronil in tilapia liver S9, suggesting that tilapia selectively metabolized R -(−)-fipronil. The CYP1A1 isozyme exhibited the highest binding capacity to R -(−)-fipronil and S -(+)-fipronil (binding energy ‒9.39 and ‒9.17 kcal/mol, respectively), followed by CYP1A2 (‒7.30 and ‒6.94 kcal/mol, respectively) and CYP3A4 (‒7.16 and ‒6.91 kcal/mol, respectively). The results of in vitro metabolic assays and molecular docking were consistent, that is, CYP1A, specifically CYP1A1, exhibited a higher metabolic capacity to fipronil than CYP3A, and fish liver S9 selectively metabolized R -(−)-fipronil. The present study provides insight into the enantioselective metabolic behavior and toxicological implications of the in vitro metabolic kinetics of fipronil in fish. Environ Toxicol Chem 2022;41:230–239. © 2021 SETAC
研究领域:
环境毒理学
·
水生毒理学
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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
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Shuaibing Liu,Shiyu Zhao,XueXia Zhang,Eric Chun Yong Chan,Ziteng Wang,Hang Li,Xin Tian
Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent K m values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 μM, while V max values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent K m value for metabolism of infigratinib to CQM157 by HLM is 0.049 μM, while the V max value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.
研究领域:
药理学
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临床医学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Liu Shuaibing,Hou Lei,Li Cai,Zhao Yibo,Yao Xia,Zhang Xiaojian,Tian Xin
Ticagrelor is the first reversibly binding, direct-acting, oral P2Y12 receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal microsomes (HIM), was well characterized in the current study. The inhibition potential of human major UGTs by ticagrelor and ticagrelor-O-glucuronide was explored. The inhibitory effects of ticagrelor-O-glucuronide on cytochrome P450s (CYPs) enzymes were investigated as well. Ticagrelor glucuronidation exhibits substrate inhibition kinetics in both HLM and HIM with apparent Km values of 5.65 and 2.52 μM, Vmax values of 8.03 and 0.90 pmol min−1·mg protein−1, Ksi values of 1,343.0 and 292.9 respectively. The in vitro intrinsic clearances (Vmax/Km) for ticagrelor glucuronidation by HLM and HIM were 1.42 and 0.36 μl min−1·mg protein−1, respectively. Study with recombinant human UGTs suggested that multiple UGT isoforms including UGT1A9, UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 are involved in the conversion of ticagrelor to ticagrelor-O-glucuronide with UGT1A9 showing highest catalytic activity. The results were further supported by the inhibition studies on ticagrelor glucuronidation with typical UGT inhibitors in pooled HLM and HIM. Little or no inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 by ticagrelor and ticagrelor-O-glucuronide was noted. Ticagrelor-O-glucuronide also exhibited limited inhibitory effects toward CYP2C8, CYP2D6 and CYP3A4. In contrast, ticagrelor-O-glucuronide weakly inhibited CYP2B6, CYP2C9 and CYP2C19 activity with apparent IC50 values of 45.0, 20.0 and 18.8 μM, respectively. The potential of ticagrelor-O-glucuronide to cause drug-drug interactions warrant further study.
研究领域:
药理学
·
药物代谢
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临床药学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Shuaibing Liu,Ziteng Wang,Eric Chan,Yibo Zhao,Jian Kang,Xiaojian Zhang,Xin Tian
Vicagrel, an antiplatelet drug candidate targeting platelet P2Y 12 receptor and has finished its phase II clinical trial . The inhibition of six major cytochrome P450 enzymes (P450) (CYP2B6, CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 , and CYP3A4) and six UDP-glucuronosyltransferases (UGT) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) by vicagrel was evaluated using pooled human liver microsomes and specific probe substrates. Physiology-based pharmacokinetic (PBPK) simulation was further applied to predict the in vivo drug-drug interaction (DDI) potential between vicagrel and bupropion as well as S-mephenytoin. The results suggested that vicagrel inhibited CYP2B6 and CYP2C19 potently with apparent IC 50 values of 1.6 and 2.0 μM, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of CYP2B6-catalyzed bupropion hydroxylation and noncompetitive inhibition of CYP2C19-mediated S-mephenytoin 4′-hydroxylation with K i values of 0.19 μM and 1.2 μM, respectively. Vicagrel displayed profound time-dependent inhibition towards CYP2B6 with maximal rate constant of inactivation ( k inact ) and half-maximal inactivator concentration ( K I ) values of 0.062 min −1 and 1.52 μM, respectively. No time-dependent inhibition by vicagrel was noted for CYP2C19. For UGT, negligible to moderate inhibition by vicagrel was observed with IC 50 values of >50.0, >50.0, 28.2, 8.7, >50.0 and 28.2 μM for UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of UGT1A6-catalyzed N-Acetylserotonin β-D-glucuronidation with a K i value of 5.6 μM. No time-dependent inhibition by vicagrel was noted for UGT1A6. PBPK simulation indicated that neither altered AUC nor C max of bupropion and S-mephenytoin was observed in the presence of vicagrel. Our study provides inhibitory constants for future DDI prediction between vicagrel and drug substrates of CYP2B6, CYP2C19 and UGT1A6. In addition, our simulation suggests the lack of clinically important DDI between vicagrel and bupropion or S-mephenytoin.
研究领域:
药理学
·
制药学
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临床试验
✓ 已验证
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）