WATER RESEARCH
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2025
·
IF 12.4
Yan Cai,Xiaoci Li,Peizeng Yang,Jing Chen,Junhe Lu,Jean-Marc Chovelon,Yuefei Ji
As one of benzophenone-derived drugs, benzbromarone (BBM) has been widely used to reduce blood uric acid, treat gout, and gouty arthritis. Understanding the transformation and fate of BBM in natural and engineered systems is critical for its ecological risk assessment. In this study, we systematically investigated the photochemical behavior of BBM in aqueous solutions under laboratory UV 254 irradiation. UV-vis spectra show that an aqueous solution of BBM is capable of absorbing UV photons at 200 - 400 nm. Spectroscopic titration indicates that BBM with a p K a value of 4.83 ± 0.17 is present mainly as the phenolate form under circumneutral conditions. BBM undergoes rapid direct photolysis when exposed to UV 254 irradiation and the quantum yields were determined to be 0.0105 and 0.0196 mol E −1 for phenol and phenolate forms, respectively. The heavy atom effect of bromine and spin-orbit coupling effect of aromatic ketone make dibromophenol and carbonyl moieties the critical chromophores accounting for the high photoreactivity of BBM. Laser flash photolysis and electron paramagnetic resonance studies suggest that the photolysis of BBM is initiated by ultrafast photodebromination and Norrish I cleavage. The high yield of bromide determined by ion chromatograph highlights the importance of photodebromination. Due to the light screening effect of wastewater components, the photolysis of BBM in hospital wastewater is inhibited. Photo-induced modification of the dibromophenol moiety of BBM likely generates photoproducts showing toxicity to luminescent bacteria. Overall, our results reveal that photochemical reaction under UV irradiation plays an important role in the attenuation of BBM in engineered water.
研究领域:
环境科学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
·
IF 5.1
Kaiji Li,Jinchao Wang,Yalong Gao,Xin Chen,Ruilong Peng,Lei Li,Cong Wang,Tuo Li,Shu Zhang,Guili Yang,Jianning Zhang
Aims Traumatic brain injury-induced coagulopathy (TBI-IC) frequently occurs after TBI, exacerbating the severity of TBI and affecting patient prognosis. Benzbromarone (BBR) is commonly used to treat hyperuricemia; however, its protective effects against TBI-IC remain unknown. Therefore, we explored whether BBR could improve TBI. Materials and methods C57BL/6 wild-type mice were subjected to fluid percussion injury to mimic TBI, and BBR was administered intraperitoneally 30 min after TBI. Magnetic resonance imaging (MRI) and Evans blue dye extravasation were used to assess the prognosis, tail bleeding time, ELISA, and coagulation tests assess coagulation function. We further explored the potential mechanism by which BBR alleviates hypercoagulation after TBI using flow cytometry. Key findings The intraperitoneally injected BBR group showed improved survival and neurological severity scores compared to the TBI group. Subsequently, we found that hypercoagulability developed 3 h after TBI and that the administration of BBR improved this hypercoagulability. BBR also reduced the degree of platelet phosphatidylserine (PS) exposure after TBI, platelet activation, and Ca2+ overload, in addition to inhibition of scramblase activity in procoagulant platelets. Significance Our findings indicate that BBR reduces PS externalization by inhibiting TMEM16F expression, thereby improving blood hypercoagulability after TBI.
研究领域:
神经科学
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药理学
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血液学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2017
·
IF 2.603
Lingli He,Chuan Li,Xuyuan Liu,Qingqing Yang,Haizhi Zhang,Weiren Xu,Luyong Zhang,Changxiao Liu
Benzbromarone is a uricosuric drug metabolized predominantly by cytochrome P450 2C9 from in vitro findings. Human CYP2C9 exhibits extensive genetic polymorphism and numbers of clinic studies have demonstrated that CYP2C9 genetic polymorphism has a significant influence on the pharmacokinetics of benzbromarone. But in vitro study on the interaction between CYP2C9 allelic isoforms and benzbromarone was rare. Here, an LC–MS/MS method was established and validated to determine the concentration of benzbromarone in different CYP2C9 enzyme incubation systems for the drug-enzyme interaction study. By selecting appropriate internal standard and optimizing separation system, including mobile phase , sample solvent and gradient elution condition, this LC–MS/MS method was developed with fine linearity (r 2 ≥ 0.996), good reproducibility (RSD ≤ 6.6%), high stability (92.37–114.67%), efficient recovery (91.23–109.82%) and acceptable matrix effect (110.54–115.31%). Based on this method, the interaction between 3 CYP2C9 allelic isoforms and benzbromarone was researched by kinetics parameters (K m , V max , Cl int ). As a result, CYP2C9*1 displayed the highest metabolic activity towards benzbromarone, CYP2C9*2 showed a little lower catalytic activity than CYP2C9*1 (relative clearance/*1 = 85.86%), CYP2C9*3 showed the lowest catalytic activity (relative clearance/*1 = 21.57%). The result illustrated that various CYP2C9 allelic isoforms showed different enzymatic activities towards benzbromarone, which could offer effective consultation for personalized administration in clinic.
研究领域:
药理学
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医学遗传学
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产品关联
DOI
PubMed
高影响因子
Journal of Veterinary Science
·
2025
·Vol. 26
·期 4
·e34
·
IF 1.5
ShaoJun Zheng,YaQin Bu,Sheng Li,NaiDong Chen
Importance Hyperuricemia (HUA) is a major metabolic disorder in poultry, leading to gout and kidney damage, which affects farm productivity. Accordingly, understanding the pharmacodynamics (PD) and pharmacokinetics (PK) of uric acid-lowering drugs is essential for improving the treatment strategies in poultry. Objective This study examined the PD and PK characteristics of allopurinol and benzbromarone, two uric acid-lowering drugs, in a quail model of HUA. Methods A hyperuricemic quail model was established using a high-purine diet. Allopurinol and benzbromarone were administered orally. Blood samples were taken and analyzed for the drug concentrations using high-performance liquid chromatography. Pathological examinations were conducted to assess kidney damage. Results Both drugs lowered the serum uric acid levels. On the other hand, the allopurinol treatment exhibited lower urea and creatinine levels than benzbromarone, indicating potential advantages in reducing kidney damage. Consistent with these findings, the pathological examinations revealed more pronounced kidney damage in the benzbromarone-treated group than in the allopurinol group. PK analysis showed that allopurinol exhibited faster absorption and elimination kinetics than benzbromarone. Both drugs showed a wide distribution in various tissues, with allopurinol and its active metabolite displaying higher excretion levels. Conclusions and Relevance This paper reports the absorption, distribution, metabolism, and excretion processes of allopurinol and benzbromarone in a quail model of HUA. These findings help better understand the PK characteristics of these drugs and promote the use of high uric acid therapy in poultry. In addition, this quail model is a valuable tool for future research on HUA and drug interventions.
研究领域:
兽医学
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药理学
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代谢疾病
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家禽健康
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药物代谢
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jianan Yang,Tonglian Jiang,Xun Lu,Xiang li,Xuling Zhou,Xinxin Guo,Chengxin Ma,Xiaobei Xie,Dongxiao Li,Siqi Yu,Jiayi An,Binghai Zhao,Hongzhi Li
Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.
研究领域:
肾病学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
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IF 3.831
Yong Tianqiao,Chen Shaodan,Xie Yizhen,Chen Diling,Su Jiyan,Shuai Ou,Jiao Chunwei,Zuo Dan
Ganoderma applanatum (G. applanatum) dispels wind to eliminate dampness and exhibited nephron- and liver-protective effects as noted in Chinese herbal classic literature; it might also affect hyperuricemia. Therefore, we examined the hypouricemia effects and mechanisms underlying G. applanatum on chemical-induced hyperuricemia in mice. Ethanol (GAE) and water (GAW) extracts were prepared by extracting G. applanatum in ethanol (GAE), followed by bathing the remains in water to yield GAW. GAE and GAW were administered orally at different doses to hyperuricemia mice, while allopurinol and benzbromarone served as positive controls. Both GAE and GAW showed remarkable hypouricemia activities, rendering a substantial decline in the SUA (serum uric acid) level in hyperuricemia control (P < 0.01). Moreover, the urine uric acid (UUA) levels were enhanced by GAE and GAW. In contrast to the evident renal toxicity of allopurinol, GAE and GAW did not show a distinct renal toxicity. Almost no suppressing effect was observed on the XOD activities. However, compared to the hyperuricemia control, OAT1 was elevated remarkably in mice drugged with GAE and GAW, while GLUT9 was significantly decreased. Similar to benzbromarone, GAE decreased the URAT1 protein levels significantly (P < 0.01), while GAW did not display a similar effect. GAE and GAW downregulated the level of CNT2 proteins in the gastrointestinal tract of hyperuricemia mice. Thus, G. applanatum produced outstanding hypouricemic effects, mediated by renal OAT1, GLUT9, and URAT1 and gastrointestinal CNT2 that might elevate urine uric secretions and decline in the absorption of purine in the gastrointestinal tracts. G. applanatum showed little negative influence on inner organs. By docking screening, four top-ranked compounds were identified that necessitated further investigation.Compounds: potassium oxonate, hypoxanthine, allopurinol, benzbromarone.
研究领域:
药理学
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医学
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分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2016
·Vol. 44
·期 4
·607-615
·
IF 3.21
Kai Wang,Hui Wang,Ying Peng,Jiang Zheng
Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.
研究领域:
药理学
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毒理学
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药物代谢
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DOI
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
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药物化学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY IN VITRO
·
2024
·
IF 2.6
Jia-hong Liang,Xiao-lei Yi,Jia-min Gong,Zuo Du
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
研究领域:
药理学
·
临床药理学
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药物代谢
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACOLOGY
·
2023
·Vol. 103
·期 4
·241-254
·
IF 3.6
Jian Gao,Hao Yin,Yanqun Dong,Xintong Wang,Yani Liu,KeWei Wang
The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 μM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing β1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 μM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies.
研究领域:
药理学
·
肺科学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2016
·
IF 3.025
Hui Wang,Yukun Feng,Qian Wang,Xiucai Guo,Wenlin Huang,Ying Peng,Jiang Zheng
Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.
研究领域:
药理学
·
毒理学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Chao Yang,Haojie Cai,Xinying Zhu,Lei Zhang,Jing Li
Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A / B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC 50 = 0.037 ± 0.001 μM) and URAT1 (IC 50 = 546.70 ± 32.60 μM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15 . Especially, for II15 , the IC 50 of XOR is 0.006 ± 0.000 μM, superior to that of febuxostat (IC 50 = 0.008 ± 0.000 μM), IC 50 of URAT1 is 12.90 ± 2.30 μM, superior to that of benzbromarone (IC 50 = 27.04 ± 2.55 μM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.
研究领域:
药理学
·
药物化学
·
药物发现
✓ 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）