CHEMICAL RESEARCH IN TOXICOLOGY
·
2023
·
IF 4.1
Aixuan Wang,Qiang Zhao,Minglu Liu,Yang Wang,Guode Zhao,Weiwei Li,Ying Peng,Jiang Zheng
Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.
研究领域:
药理学
·
毒理学
·
药物代谢
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2018
·
IF 3.412
Jianqiang Sun,Qiong Chen,Zhuxiu Qian,Yan Zheng,Shuai Yu,Anping Zhang
Plants can extensively uptake organic contaminants from soil and subsequently transform them into various products. Those compounds containing hydroxyl may undergo direct conjugation with endogenous biomolecules in plants, and potentially be preserved as conjugates, thus enabling overlooked risk via consumptions of food crops. In this study, we evaluated the uptake and metabolism of 2,4-dibromophenol (DBP) by both carrot cells and whole plant. DBP was completely removed from cell cultures with a half-life of 10.8 h. Four saccharide conjugates, three amino acid conjugates, and one phase I metabolite were identified via ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry analysis. The dibromophenol glucopyranoside (glucose conjugate) was quantitated by synthesized standard and accounted for 9.3% of the initial spiked DBP at the end of incubation. The activity of glycosyltransferase was positively related to the production of 2,4-dibromophenol glucopyranoside (p = 0.02, R2 = 0.86), implying the role of enzymatic catalysis involved in phase II metabolism.
研究领域:
植物学
·
环境科学
·
食品科学
✓ 已验证
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Kaixuan Li,Guode Zhao,Lan Yang,Xingyu Gao,Yudi Jia,Yang Wang,Xiaohong Zhang,Weiwei Li,Ying Peng,Jiang Zheng
4-Methylquinoline (4-MQ) is a quinoline derivative widely present in groundwater and soil and has been reported to be genotoxic. The mechanisms of the toxic action remain unknown. This study aimed to elucidate the metabolic activation of 4-MQ and to determine the possible role of reactive metabolites in 4-MQ-induced liver injury in rats. In the present study, a hydroxylation metabolite (M1), a GSH conjugate (M2) and an NAC conjugate (M3) derived from 4-MQ were detected in vitro and in vivo . The structures of the two conjugates were verified by chemical synthesis, mass spectrometry, and nuclear magnetic resonance. CYP3A4 was found to dominate the hydroxylation of 4-MQ. Sulfotransferases also participated in the metabolic activation of 4-MQ. Pretreatment of primary hepatocytes with ketoconazole (KTC) or 2,6-dichloro-4-nitrophenol (DCNP) not only reduced the production of GSH conjugate M2 but also decreased the susceptibility of hepatocytes to the cytotoxicity of 4-MQ. Urinary NAC conjugate M3 was found in rats given 4-MQ, and M3 may be a potential biomarker for 4-MQ exposure.
研究领域:
毒理学
·
药理学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2021
·
IF 3.739
Yutong You,Xu Wang,Kaiqi Ma,Jiaru Li,Ying Peng,Jiang Zheng
Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX’s toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.
研究领域:
药理学
·
毒理学
·
肝脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2014
·
IF 2.829
Guo Ma,Jiayuan Lin,Weimin Cai,Bo Tan,Xiaoqiang Xiang,Ying Zhang,Peng Zhang
Bilirubin, an important endogenous substances and liver function index in humans, is primarily eliminated via UGT1A1-catalyzed glucuronidation. Instability of bilirubin and its glucuronides brings substantial technical challenges to conduct in vitro bilirubin glucuronidation assay. In the present study, we developed a simple and robust HPLC method for simultaneous determination of unconjugated bilirubin (UCB) and its multiple glucuronides, i.e. bilirubin monoglucuronides (BMGs, including BMG1 and BMG2 isomers) and diglucuronide (BDG) in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human UGT1A1 enzyme (UGT1A1) incubation systems, and applied it to study in vitro bilirubin glucuronidation. UCB, BMG1, BMG2, BDG and their isomers in the incubation mixtures were successfully separated using a C18 column with UV detection at 450 nm and mobile phase consisted of 0.1% formic acid in water and acetonitrile by a linear gradient elution program. Assay linearities of bilirubin were confirmed in the range 0.01–2 μM. Precision of UCB, BMG1, BMG2 and BDG ( n = 5) at low, medium and high concentration was within the range of RSD 0.4–3.7%, accuracy expressed in the mean assay recoveries of them ( n = 5) ranged from 92.8 ± 1.5% to 104.3 ± 2.2% for intra- and inter-day assays and the mean extraction recoveries of them ( n = 5) were above 91.5 ± 1.0%. Stability of bilirubin and its glucuronides was satisfactory at 37 °C in the incubation solutions during the reaction (30 min), 25 °C for 24 h and −70 °C for 7 d in the processed incubation samples with methanol. Furthermore, we established stable, reliable in vitro incubation systems and optimized the incubation conditions to characterize the kinetics of bilirubin glucuronidation by RLM, HLM and UGT1A1, respectively. The kinetic parameters of formation of total bilirubin glucuronides (TBG, the sum of BMG1, BMG2 and BDG) were as follows: K m of 0.45 ± 0.016, 0.40 ± 0.022, 0.44 ± 0.018 μM, V max of 2.65 ± 0.057, 1.86 ± 0.029, 2.95 ± 0.036 nmol/mg/min, CL int of 5.92 ± 0.22, 4.70 ± 0.079, 6.72 ± 0.27 mL/mg/min by RLM, HLM and UGT1A1, respectively. Bilirubin glucuronidation obeyed the Hill equation by RLM and the Michaelis–Menten equation by HLM and UGT1A1 in the range of substrate concentration selected, respectively. In addition, the relative proportions between BDG and BMGs were in connection with enzyme sources (e.g. RLM, HLM and UGT1A1) and bilirubin concentration.
研究领域:
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Minyi Yang,Rongye Jia,Yuxuan Liu,Hengkun Tang,Huijuan Wu,Jun Yuan,Rongzhi Wang
Furosine, a hazardous compound mainly produced by the Maillard reaction in food at high temperatures, has been shown to exert cytotoxic effects on cells and cause liver damage after excessive consumption. Hence, it is desirable to develop correlative sensitive and robust immunoassays for furosine detection in real-world samples. In this study, Ovalbumin-furosine (OVA-furo) conjugates were employed as the immunogens for animal immunization, and a hybridoma (1C3) secreting an anti-furosine monoclonal antibody (mAb) was successfully screened. The purified 1C3 mAb exhibited high specificity and affinity (7.4 × 10 8 L/mol), and an indirect competitive ELISA (ic-ELISA) based on the 1C3 mAb was developed for the detection of furosine. The linear detection range of the ic-ELISA was 6.03–817.85 ng/mL, with a limit of detection (LOD) value of 2 ng/mL. Colloid gold nanospheres(AuNP-) and nanoflower gold-particles(AuNF)-based strips were also established based on this antibody, which had qLOD values and linear ranges of 40 and 20 ng/mL and 40–140 and 20–90 ng/mL, respectively. All the immunoassays showed good detection performance, indicating that these immunoassays have the potential for practical application for the inexpensive detection of furosine in real-world samples.
研究领域:
食品科学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2024
·
IF 4.8
Sun Chen,Zhang Mingyu,Guan Chunjing,Li Weiwei,Peng Ying,Zheng Jiang
Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N -acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat & human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6’ of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10–400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.
研究领域:
药理学
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毒理学
·
药物代谢
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2021
·Vol. 29
·期 17
·24589-24598
·
IF 4.223
Zhang Jun,Wan Yi-ping,Liu Ze-hua,Wang Hao,Dang Zhi,Liu Yu
It is important to keep natural estrogen conjugates (C-NEs) intact in aqueous environmental sample before sample preparation; otherwise, this may influence the accurate determination of NEs. Therefore, this work thoroughly investigated the stability of C-NEs in three different aqueous environmental samples under four different storage conditions, room temperature, low temperature of 4 °C, low pH of 3, and addition of HgCl 2 at 2 g/L. Results showed that C-NEs in aqueous sample were easily deconjugated under low temperature of 4 °C, which has been widely used in sample collection and storage. Both the low pH of 3 and addition of HgCl 2 at 2 g/L under room temperature could keep C-NEs intact in domestic wastewaters and river water within 36 h, but the latter could keep C-NEs stable longer. This work is the first to show that low pH of 3 alone could keep C-NEs intact, which suggested that the combined condition at low temperature of 4 °C that has been widely used could be omitted. Meanwhile, compared to pH adjustment, addition of 2 g/L HgCl 2 into aqueous sample is more convenient and practical for 24-h composite sampling, which may be widely applied.
研究领域:
环境科学
·
生物学
·
分析化学
✓ 已验证
DOI
PubMed
高影响因子
Materials Today Communications
·
2024
·
IF 3.7
Zixuan Xiao,Keying Chen,Tong Lin,Pengkai Zhao,Haixia Wang,Zhiqiang Su
ABSTRACT Breast cancer become the most prevalent malignancy and is rising up to the first leading cause of cancer-related mortality among the female people globally. Approaches for safe, specific targeting and efficient inhibition of breast cancer cells, are urgently demanded for lifting the survival rate of breast tumor-bearing patients. Herein, a versatile hydrogel drug carrier consisting of doxorubicin (DOX)-loaded hydrogel microsphere and carbon dots (CDs)-loaded peptide nanowires (DOX@PEG/PNFs-CDs) was constructed, presenting specific targeting and synergistic anti-cancer cell potencies. The hydrogel PEG microspheres with a rich porous structure benefited the drug loading efficiency, demonstrating good biodegradability and higher drug release efficiency at acidic environment. Benefiting from the RGD group of the peptide nanowires, the drug-loaded system specific targeted onto the MDA-MB-231 cells, subsequently promoting the synergistic inhibition of the cancer cell growth by DOX and metformin derived CDs. This all-in-one smart drug carrier post a promising strategy for breast cancer treatment.
研究领域:
肿瘤学
·
药剂学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
LWT-FOOD SCIENCE AND TECHNOLOGY
·
2025
·
IF 6.6
Xiaoke Peng,Xiaojia Yan,David Julian McClements,Shuai Chen,Cuicui Ma,Xuebo Liu,Guoqiang Zhang,Fuguo Liu
The objective of this study was to prepare dendrobium officinale polysaccharide-epigallocatechin-3-gallate (DOP-EGCG) covalent conjugates and non-covalent complexes to enhance the antioxidant properties of the polysaccharide. The conjugates were synthesized via free radical induction, whereas the complexes were formed through physical mixing. The structure and properties of the conjugates and complexes were then characterized. C-H bonds and hydrogen bonds were found to play a crucial role in the formation of the conjugates. Conjugating DOP and EGCG decreased the crystallinity of the polysaccharide and altered the crystal morphology of the polyphenol. The thermal stability of DOP in the EGCG complexes (99.2 °C) was lower than that of free DOP (103.0 °C), whereas that of the DOP in the EGCG conjugates was higher (113.7 °C). The conjugation of EGCG led to an increase in its phenolic content (112.9 ± 1.8 g/kg), which enhanced its antioxidant properties. Indeed, the conjugates had higher antioxidant properties, as seen by an increase in free radical scavenging, reactive oxygen species quenching, and reducing ability, than the complexes. The present study demonstrated that the formation of polysaccharide-polyphenol conjugates could enhance the antioxidant properties of DOP, thereby expanding its range of application as a functional ingredient in foods and beverages.
研究领域:
食品科学
·
植物化学
·
营养学
✓ 已验证
产品关联
DOI
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2015
·
IF 2.577
Meina Chi,Ying Peng,Jiang Zheng
Bakuchiol belongs to a family of monoterpene phenols occurring in plant Psoralea corylifolia L., a traditional herbal medicine. Bakuchiol has also demonstrated multiple pharmacologic activities. However, metabolism of bakuchiol had never been investigated. The major objective of the present study was to study the metabolic pathways of bakuchiol in order to identify potential reactive metabolites. A total of five glutathione (GSH) conjugates (M1-M5) were detected in rat/human liver microsomes containing NADPH, GSH, and bakuchiol. M1 and M2 resulted from GSH conjugated on the phenol ring. M3, M4, and M5 were derived from GSH adducted on the side chain. The results displayed that bakuchiol can be bioactivated by oxidation of the phenol moiety to the corresponding ortho -quinone and by epoxidation of the aliphatic side chain to epoxide metabolites. No bakuchiol-derived GSH conjugates were detected in urine of rats given bakuchiol, but six corresponding cysteinylglycine (Cys–Gly) conjugates and mercapturic acids were observed instead. A 2’-iodoxybenzoic acid-mediated oxidation reaction of bakuchiol in the presence of GSH produced M1 and M2, and m -chloroperoxybenzoicacid-mediated oxidation of bakuchiol trapped with GSH generated M3 and M4. The four synthetic metabolites were detected in microsomal incubations. In addition, recombinant P450 enzyme incubations showed that CYP 1A2 was the predominant P450 responsible for the metabolism of bakuchiol. In summary, our results demonstrated that bakuchiol can be bioactivated to quinone and epoxide metabolites. These findings facilitate the understanding of the mechanisms of bakuchiol-induced cytotoxicity.
研究领域:
药理学
·
毒理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2025
·
IF 9.8
Yue Chen,Jingjing Huang,Yexu Wu,Xiaoqiang Chen
The O/W interface behavior of tea polysaccharide conjugate-egg white protein (TPC/EWP) nanoparticles was investigated and a bigel system was constructed. The results showed that TPC/EWP nanoparticles with better storage and thermal stability were successfully prepared, in which the mass ratio of tea polysaccharide conjugate to egg white protein of 3:1 helped to enhance the diffusion, penetration and rearrangement processes. To make O/W interfacial layer had higher viscoelasticity and expansion modulus. The nanoparticle-based bigel exhibited fine texture and was not easy to flow. In addition, the tight gel network endowed the bigels with strong rheological properties and stability. These results establish a theoretical foundation for further investigation into O/W interface behavior of TPC/EWP nanoparticles. The bigels' excellent gel properties and stability provide a new direction for applying the bigel as a novel food in the food field.
研究领域:
食品科学
·
界面化学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）