DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 8
·919-927
·
IF 3.354
Xu Mao,Jian Wang,Qian Wang,Lan Yang,Yilin Li,Hao Lin,Ying Peng,Jiang Zheng
The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a Ki value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with Ki and KI values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2–induced genotoxicity.
研究领域:
药理学
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毒理学
·
生物化学
·
酶学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2022
·Vol. 50
·期 12
·1464-1471
·
IF 3.579
Jie Yang,Shicheng Fan,Yifei Zhang,Min Huang,Yue Gao,Huichang Bi
Peroxisome proliferator-activated receptor α (PPARα) is closely related to lipid metabolism and various liver diseases. Previous study has shown that chronic treatment with PPARα agonist WY-14643 can induce liver tumors in rodents, but the implications of this process on lipid metabolism in the liver remain unclear. Thus, this study aimed to explore the influences of chronic treatment with WY-14643 on the liver and hepatic lipid metabolism. Wild-type C57BL/6 mice were treated with WY-14643 (100 mg/kg/week, i.p.) or corn oil, and liver and serum samples were collected for testing after 42 weeks of WY-14643 treatment. The results showed that hepatomegaly, liver tumors with mild liver injury, and hepatocyte proliferation were induced in mice treated with WY-14643. The mRNA and protein expression levels of PPARα downstream targets acyl-CoA oxidase 1 and cytochrome P450 4A were significantly upregulated in the WY-14643–treated group. Lipidomic analysis revealed that chronic treatment with WY-14643 disturbed lipid homeostasis, especially triglycerides (TGs), which were significantly elevated after WY-14643 treatment. Moreover, TG homeostasis-related genes were significantly increased in the WY-14643–treated group. In conclusion, these findings demonstrated that hepatomegaly and liver tumors induced by chronic treatment with WY-14643 in mice are accompanied by hepatocyte proliferation and TG accumulation.
研究领域:
药理学
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肝病学
·
分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2018
·Vol. 46
·期 11
·1538-1545
·
IF 3.64
Jiangming Deng,Lianxia Guo,Baojian Wu
Human CYP2A6 (Cyp2a5 in mice) plays an important role in metabolism and detoxification of various drugs and chemicals. Here, we investigated a potential role of peroxisome proliferator-activated receptor γ (Ppar-γ) in circadian regulation of the Cyp2a5 enzyme. We first showed that Cyp2a5 mRNA and protein in mouse liver displayed robust circadian oscillations. Consistent with a circadian protein pattern, Cyp2a5-mediated 7-hydroxylation of coumarin was circadian time–dependent. Formation of 7-hydroxycoumarin was more extensive at a dosing time of Zeitgeber time 2 (ZT2) than that at ZT14. Interestingly, the nuclear receptor Ppar-γ was also a circadian gene. Circadian Ppar-γ protein level was strongly correlated with the Cyp2a5 mRNA level (r = 0.989). Furthermore, Ppar-γ activation (by a selective agonist, rosiglitazone) upregulated Cyp2a5 expression in Hepa-1c1c7 cells, whereas Ppar-γ knockdown downregulated Cyp2a5 expression. Also, Ppar-γ knockdown blunted the rhythmicity of Cyp2a5 mRNA in serum-shocked Hepa-1c1c7 cells. In addition, a combination of promoter truncation analysis, mobility shift, and chromatin immunoprecipitation assays revealed that Ppar-γ directly bound to a PPAR response element (i.e., the −1418- to −1396-bp region) within Cyp2a5 promoter and activated the gene transcription. Taken together, Ppar-γ was a transcriptional activator of Cyp2a5, and its rhythmic expression contributed to circadian expression of Cyp2a5.
研究领域:
药理学
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分子生物学
·
昼夜节律生物学
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PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2017
·Vol. 45
·期 12
·1354-1363
·
IF 4.242
Hui Wang,Ying Peng,Tingjian Zhang,Qunsheng Lan,Huimin Zhao,Wenbao Wang,Yufei Zhao,Xu Wang,Jianxin Pang,Shaojie Wang,Jiang Zheng
Benzbromarone (BBR) is effective in the treatment of gout; however, clinical findings have shown it can also cause fatal hepatic failure. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) that reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives, fluorinated BBR (6-F-BBR), chlorinated BBR (6-Cl-BBR), and brominated BBR (6-Br-BBR), to decrease the potential for cytochrome P450–mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that 6-F-BBR achieved favorable uricosuric effect, while 6-Cl-BBR and 6-Br-BBR showed weak uricosuric efficacy. Additionally, 6-F-BBR elicited much lower hepatotoxicity in mice. Fluorination of BBR offered advantage to metabolic stability in liver microsomes, almost completely blocked the formation of epoxide metabolite(s) and protein covalent binding, and attenuated hepatic and plasma glutathione depletion. Moreover, the structural manipulation did not alter the efficacy of BBR. This work provided solid evidence that the formation of the epoxide(s) is a key step in the development of BBR-induced hepatotoxicity.
研究领域:
药理学
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毒理学
·
药物化学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2018
·
IF 3.64
Danyi Lu,Dong Dong,Qian Xie,Zhijie Li,Baojian Wu
UDP-glucuronosyltransferases (UGTs) play an important role in metabolism and detoxification of amine-containing chemicals. However, the disposition mechanisms for amines via UGT metabolism are not fully clear. Here we aim to investigate a potential role of UGT2B10 in N-glucosidation, and to determine the transporters for excretion of N-glucosides. We first established a HEK293 cell line stably overexpressing UGT2B10. Incubation of mianserin or cyclizine with the cells generated one N-glucuronide and one N-glucoside. Chemical inhibition (using specific chemical inhibitor Ko143) and biological inhibition (using specific shRNA) of BCRP resulted in a significant reduction in efflux of N-glucuronide. Similar results were observed when MRP4 was inhibited. Furthermore, inhibition of BCRP led to increased intracellular N-glucoside, whereas inhibition of MRP4 caused no changes in disposition of N-glucosides. The data overall indicated that BCRP not MRP4 was responsible for excretion of N-glucosides, whereas both BCRP and MRP4 contributed to excretion of N-glucuronides. Interestingly, down-regulation of N-glucuronidation led to increased N-glucosidation in the cells, supporting the glucosidation as a potential complementary pathway for conventional glucuronidation. In conclusion, UGT2B10 was for the first time identified as a N-glucosidation enzyme. Generated N-glucosides were excreted primarily by the BCRP transporter.
研究领域:
药理学
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生物化学
·
分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2022
·Vol. 50
·期 6
·809-818
·
IF 3.579
Zitao Guo,Mengling Liu,Jian Meng,Yaru Xue,Qi Huang,Yuandong Zheng,Yali Wu,Zhendong Chen,Jinghua Yu,Dafang Zhong,Guangze Li,Xiaoyan Chen,Xingxing Diao
Excretion of [14C]HR011303-derived radioactivity showed significant species difference. Urine (81.50% of dose) was the main excretion route in healthy male subjects, whereas feces (87.16% of dose) was the main excretion route in rats. To further elucidate the underlying cause for excretion species differences of HR011303, studies were conducted to uncover its metabolism and excretion mechanism. M5, a glucuronide metabolite of HR011303, is the main metabolite in humans and rats. Results of a rat microsome incubation study suggested that HR011303 was metabolized to M5 in the rat liver. According to previous studies, M5 is produced in both human liver and kidney microsomes. We found that M5 in the human liver can be transported to the blood by multidrug resistance-associated protein (MRP) 3, and then the majority of M5 can be hydrolyzed to HR011303. HR011303 enters the human kidney or liver through passive diffusion, whereas M5 is taken up through organic anion transporter (OAT) 3, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. When HR011303 alone is present, it can be metabolized to M5 in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH) and excreted into bile as M5 in SCRH. Using transporter inhibitors in sandwich-cultured model and membrane vesicles expressing MRP2 or Mrp2, we found that M5 was a substance of MRP2/Mrp2, and the bile efflux of M5 was mainly mediated by MRP2/Mrp2. Considering the significant role of MRP3/Mrp3 and MRP2/Mrp2 in the excretion of glucuronides, the competition between them for M5 was possibly the determinant for the different excretion routes in humans and rats.
研究领域:
药理学
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毒理学
·
药物代谢动力学
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PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 12
·1628-1641
·
IF 3.9
Qiushuang Sun,Yating Guo,Wenjun Hu,Mengdi Zhang,Shijiao Wang,Yuanyuan Lei,Haitao Meng,Ning Li,Pengfei Xu,Zhiyu Li,Haishu Lin,Fang Huang,Zhixia Qiu
The hepatic SLC13A5/SLC25A1-ATP–dependent citrate lyase (ACLY) signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1, and ACLY and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo. Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusion, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic PXR-SLC13A5/ACLY signaling axis, while PXR, a key regulator in drug metabolism may be involved in the pathogenesis of NAFLD.
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PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2011
·Vol. 39
·期 4
·667-674
·
IF 3.716
Zhongjian Chen,Meng Chen,Hao Pan,Siyuan Sun,Liping Li,Su Zeng,Huidi Jiang
Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol- O -methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor , entacapone , the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2013
·Vol. 41
·期 5
·1082-1093
·
IF 3.361
Hao Pan,Liqiang Gu,Siyuan Sun,Zhongjian Chen,Hui Zhou,Su Zeng,Huidi Jiang
Bis(4-fluorobenzyl)trisulfide (BFBTS) is a promising new antitumor agent under investigation. It was metabolized rapidly in vivo in rat, but the metabolic fate and primary site of metabolism have not been clarified. In this study, we investigated the role of blood in the metabolism of BFBTS and compared the BFBTS metabolic potencies in whole blood, plasma, and red blood cells (RBCs) in vitro. Three major metabolites of BFBTS [bis(4-fluorobenzyl)disulfide, para-fluorobenzyl-mercaptan, and para-fluorobenzoic acid] were detected in RBCs and whole blood. Significant metabolism of BFBTS was observed in RBCs that were identified as the primary site of BFBTS metabolism. Thiols, including endogenous thiols and hemoglobin, were proven to be the critical factor in BFBTS metabolism. S-Fluorobenzylmercaptocysteine Hb (hemoglobin) adducts were characterized in vitro at BFBTS concentration of 250 μM and higher, whereas such Hb adducts were not detected in RBCs from Sprague-Dawley rats receiving a single intravenous injection of BFBTS at a high dose of 50 mg/kg. Liquid chromatography-tandem mass spectrometry results revealed that adduction induced by BFBTS was prone to take place at Cys125 of globin β chains. Otherwise, glutathionylation of Hb was also observed that may be attributed to the oxidative effect of BFBTS. In summary, BFBTS was unstable when it met with thiols, and RBCs were the main site of BFBTS metabolism. Hb adducts induced by BFBTS could be detected in vitro at high concentration but not in vivo even at high dose.
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PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Jia Deng,Shaoge Fu,Yifan Zhong,Ming Jiang,Tao Chen,Haili Zhao
Photonic crystal (PC) hydrogels with unique micro/nanostructures have excellent prospects in many fields, such as sensing, displays, anticounterfeiting, information encryption, and adaptive camouflage. Herein, magnetic core–shell Fe3O4/SiO2 nanoparticles with a controlled size were synthesized, followed by PC hydrogels of arbitrary structures that were fabricated via the magnetically inducing self-assembly of magnetic nanoparticles in the poly(ethylene glycol) diacrylate (PEGDA) pregel solution and a subsequent digital micromirror device (DMD)-based UV polymerization process. By controlling the size of nanoparticles and magnetic field intensity, various PC hydrogel patterns with tunable structural colors were fabricated. Combining magnetic field control with DMD-based light modulation, high-throughput preparation of structural color PC hydrogels was achieved. Furthermore, the Fe3O4/SiO2 nanoparticles were assembled into poly(2-hydroxyethyl methacrylate) (PHEMA) with solvent responsiveness. Interestingly, the obtained PC hydrogels could swell in ethanol, resulting in a change in the structural color. Meaningfully, a dual-component PC hydrogel consisting of a PEGDA pattern and a PHEMA background was fabricated, and the invisible pattern in the initial state could be displayed and hidden through cyclic exposure to ethanol and ethylene glycol. The presented strategy for constructing the PC hydrogels from Fe3O4/SiO2 nanoparticles could provide valuable insights for the development of intelligent structural color materials, which exhibit significant potential in applications such as information storage, visual sensing, and anticounterfeiting.
研究领域:
材料科学
·
纳米技术
·
光学
·
化学
·
防伪技术
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产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Mengru Zhou,Xiaoyao Ma,Jiaqi Zhang,Xuan Lu
3,5-Dimethyl-8-methoxy-3,4-dihydro-1H-isochromen-6-ol (DMD) is a polyketide compound obtained from the endophytic fungus Penicillium sp. HJT-A-10 of Rhodiola tibetica. R. tibetica is a nourishing food and also used in traditional Chinese medicine and Xizang medicine. In dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice, DMD significantly alleviated the pathological symptom of UC. Network pharmacology studies have shown that nucleotide-binding domain-like receptor family pyrin domain containing (NLRP) 3 is the primary target protein of DMD associated with anti-UC. In molecular biology studies, DMD suppressed the activation of NLRP3 and decreased the expression of downstream inflammatory proteins and pro-inflammatory cytokines in UC. The finding was further verified in knockout mice. DMD lost the effect of attenuating DSS-induced UC in NLRP3–/– mice. In conclusion, this study demonstrates that DMD reduces inflammatory response and balances the barrier integrity to attenuate UC via targeting NLRP3, and DMD is a potential natural agent or dietary supplement for attenuating UC.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
分子生物学
·
传统医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2022
·
IF 5.546
Haili Zhao,Hao Gao,Tao Chen,Linsheng Xie,Yulu Ma,Jin Sha
In the present work, programmable light pattern produced by digital micro-mirror device (DMD) spatial light modulator was employed to initiate the atom transfer radial polymerization (ATRP) for fabricating the patterned polymer brushes on the silicon substrate surface. Results from a series of characterization methods such as optical microscopy, 3D optical surface profiler, and X-ray photoelectron spectroscopy proved the poly (ethylene glycol) methyl acrylate (PEGMA) brushes with complex structures were successfully generated. The thickness of PEGMA brushes could be regulated by adjusting the DMD light modulation parameter including pattern size, gray value and exposure time. The contact angle measurements showed the PEGMA brushes could improve the hydrophilicity property of substrate surface. The antifouling property of the patterned surfaces with different shapes were tested, and the results indicated that the PEGMA brushes could effectively resist the adhesion of bovine serum albumin (BSA) protein, leading to the selective arrangement of protein. The reported method for generating the polymer brush patterns shows great potential for the manipulation of surface property in facilitating a range amount of applications from anti-biofouling coating, interface lubrication to biomimetic and smart surfaces.
研究领域:
材料科学
·
高分子化学
·
表面科学
·
生物医学工程
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高影响因子
危险品化学品经营许可证（带存储）