CHEMICO-BIOLOGICAL INTERACTIONS
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2025
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IF 5.4
Tingmin Ye,Chunping Tang,Dandan Yang,Qing Zhang,Yufen Liao,Jie Dai,Hong Tang,Changqiang Ke,Ying Peng,Yang Ye,Weiwei Li,Jiang Zheng
Bavachin (BVC), a flavonoid, is found in Psoraleae fructus (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase and aspartate transaminase in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or N -acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding o -quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH in vivo and that BVC contributes to the depletion of hepatic GSH caused by PF extract.
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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DOI
PubMed
高影响因子
XENOBIOTICA
·
2021
·
IF 1.908
Min Tian,Shenzhi Zhou,Wei Li,Jiaru Li,Lan Yang,Ying Peng,Jiang Zheng
Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant Aegle marmelos, with multiple pharmacological activities.As one component of several dietary supplements, AGL caused a series of acute and chronic liver injuries. Nevertheless, the mechanisms of AGL-induced hepatotoxicity remain unclear. This study was conducted to identify reactive metabolite(s), to determine related metabolic pathways, and define the possible association of the bioactivation with AGL cytotoxicity.A demethylation metabolite (M1) and a GSH conjugate (M2) were detected in rat liver microsomal incubations containing AGL and GSH. The two metabolites were both found in bile of rats and rat primary hepatocytes after AGL administration.Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalysing this metabolic activation.Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of AGL. The results suggest that AGL was metabolized to a p-quinone methide intermediate which could in part participate in AGL-induced cytotoxicity.
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
CHEMICAL RESEARCH IN TOXICOLOGY
·
2024
·
IF 3.7
Xinxin Guo,Mingyu Zhang,Ya Li,Zifang Ding,Minglu Liu,Weiwei Li,Ying Peng,Jiang Zheng
Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.
研究领域:
环境科学
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毒理学
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药理学
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DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2016
·Vol. 408
·期 15
·4111-4119
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IF 3.125
Xie Honglei,Liu Yuyang,Peng Ying,Zhao Dongmei,Zheng Jiang
Dauricine is a bisbenzylisoquinoline alkaloid derivative and has shown multiple pharmacological properties. Despite this, our previous study demonstrated that dauricine induced severe lung toxicity in experimental animals. Metabolic activation of dauricine to the corresponding quinone methide intermediate is suggested to play an important role in dauricine-induced cytotoxicity. Protein adduction derived from the reactive intermediate is considered to initiate the process of the toxicity. In the present study, we developed an alkaline permethylation- and mass spectrometry-based approach to detect dauricine-derived protein adduction. Protein samples were permethylated in the presence of NaOH and CH 3 I at 80 °C, followed by LC-MS/MS analysis. A thioether product was produced in the reaction. Not only does this technique quantify dauricine-derived protein adduction but also it tells the nature of the interaction between the target proteins and the reactive intermediate of dauricine. The recovery, precision, limit of detection, limit of quantity, and method detection limit were found to be 102.8 %±1.7 %, 1.89 %, 1.32 fmol/mL, 4.93 fmol/mL and 3.37 fmol/mL respectively. The surrogate recovery and surrogate RSD values were 81.5–103.0 % and 2.59 %, respectively. This analytical method has proven sensitive, selective, reliable, and feasible to assess total protein adduction derived from dauricine, and will facilitate the mechanistic investigation of dauricine and other bisbenzylisoquinoline toxicities.
Alkaline permethylation of dauricine derived protein adduct
研究领域:
药理学
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毒理学
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蛋白质组学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2025
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IF 2.9
Siyu Liu,Guode Zhao,Yingyun Xu,Yang Wang,Zifang Ding,Weiwei Li,Ying Peng,Jiang Zheng
Osthole (OST), a coumarin derivative, is one of the major components of Cnidium monnieri (L.) Cussion. OST was reported to induce apoptosis in hepatocytes. Elevated serum ALT and AST were documented in Sprague-Dawley rats after administration of OST. In the present study, OST was found to be metabolized to a phenol metabolite which was further metabolically oxidized to the corresponding quinone methide intermediate. A glutathione conjugate derived from the reactive metabolite was detected in vitro and in vivo . The structures of the metabolites were verified by chemical analysis. CYP3A4 and CYP1A2 were the major enzymes to catalyze the oxidation reactions. Pre-treatment with 1-aminobenzotriazole or ketoconazole decreased the susceptibility of primary hepatocytes to the cytotoxicity of OST. The findings provided solid evidence that the metabolic activation of OST correlated with the cytotoxicity of OST.
研究领域:
药理学
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毒理学
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DOI
PubMed
高影响因子
Toxins
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2017
·Vol. 9
·期 8
·249
·
IF 3.03
Kai Wang,Dongju Lin,Xiucai Guo,Wenlin Huang,Jiang Zheng,Ying Peng
Diosbulbin B (DIOB), a hepatotoxic furan-containing compound, is a primary ingredient inDioscorea bulbiferaL., a common herbal medicine. Metabolic activation is required for DIOB-induced liver injury. Protein covalent binding of an electrophilic reactive intermediate of DIOB is considered to be one of the key mechanisms of cytotoxicity. A bromine-based analytical technique was developed to characterize the chemical identity of interaction of protein with reactive intermediate of DIOB. Cysteine (Cys) and lysine (Lys) residues were found to react with the reactive intermediate to form three types of protein modification, including Cys adduction, Schiff’s base, and Cys/Lys crosslink. The crosslink showed time- and dose-dependence in animals given DIOB. Ketoconazole pretreatment decreased the formation of the crosslink derived from DIOB, whereas pretreatment with dexamethasone or buthionine sulfoximine increased such protein modification. These data revealed that the levels of hepatic protein adductions were proportional to the severity of hepatotoxicity of DIOB.Keywords:diosbulbin B;hepatotoxicity;protein covalent binding;metabolic activation;bromine-based analytical technique
研究领域:
药理学
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毒理学
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分析化学
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DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2017
·
IF 3.278
Yukun Feng,Hui Wang,Qian Wang,Wenlin Huang,Ying Peng,Jiang Zheng
Methyleugenol (ME), an alkenylbenzene compound, is a natural ingredient of several herbs and is used as flavoring agent in foodstuffs and fragrance in cosmetics. The hepatotoxicity, cytotoxicity, and carcinogenesis of ME have been well documented, and metabolic activation has been suggested to involve in ME-induced toxicities. The objective of this study was to identify chemical identity of interactions of protein with reactive metabolites of ME. Modification of cysteine residues of protein was observed in microsomal incubations and mice after exposure to ME. Three types of protein modification derived from the corresponding epoxide, α,β-unsaturated aldehyde, and carbonium ion of ME were detected in vitro and in vivo. The protein adduction took place in time- and dose-dependent manners. Dexamethasone, ketoconazole, and l-buthionine sulfoximine increased the protein modification induced by ME, which was proportional to the hepatotoxicity of ME. The findings facilitate the understanding of mechanism action of ME toxicities.
研究领域:
毒理学
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生物化学
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药理学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Shiyu Zhang,Bowen Gong,Rong Tan,Yufen Liao,Xin Wang,Xu Wang,Ying Liu,Ting Liu,Jun Luo,Weiwei Li,Jia Yu,Ying Peng,Jiang Zheng
8-Epidiosbulbin E acetate (EEA), a furan-containing diterpenoid lactone and key component of Dioscorea bulbifera L., has been found to induce notable liver injury in mice through CYP3A-mediated metabolic activation to a cis -enedial reactive metabolite. EEA exposure at 25, 50, 100, or 200 µM triggered apoptosis in cultured mouse primary hepatocytes, evidenced by alterations in mitochondrial and endoplasmic reticulum (ER) pathway protein levels. Pretreatment with ketoconazole, vitamin C, glutathione ethyl ester, or 4-phenylbutyric acid effectively reduced the apoptotic ratio and restored the balance of mitochondrial and ER pathway protein levels impacted by EEA in primary hepatocytes. In contrast, pretreatment with L-buthionine sulfoximine exacerbated the apoptotic ratio and altered protein levels associated with the mitochondrial and ER pathways induced by EEA. In summary, metabolic activation, GSH depletion, and ROS are implicated in the induction of apoptosis. EEA triggered apoptosis in cultured primary hepatocytes via disruption of the crosstalk between the mitochondrial and ER pathways.
研究领域:
药理学
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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
XENOBIOTICA
·
2021
·
IF 1.908
Yilin Li,Yang Wang,Na Zhang,Shenzhi Zhou,Ying Peng,Jiang Zheng
Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF.One glutathione (GSH) conjugate and one cysteine conjugate were both detected in mouse and human liver microsomal incubations containing VLF and GSH or cysteine. The two conjugates were also detected in cultured mouse primary hepatocytes and bile of rats after exposure to VLF. The in vitro and in vivo studies demonstrated that VLF was metabolized to a quinone methide intermediate reactive to GSH and cysteine residues of hepatic protein. The observed protein covalent binding revealed dose-dependency. The metabolic activation of VLF was P450-dependent, and CYP3A4 was found as the predominant enzyme involved in the bioactivation process.These findings facilitate better understanding of the metabolic activation-hepatotoxicity relationship of VLF and provide chemists with information about new potential structural alerts during drug design process.
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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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Yan He,Zihao Cheng,Jingyu Zhang,Yu Chen,Guode Zhao,Hong Tang,Yufen Liao,Tingmin Ye,Ying Peng,Weiwei Li,Jiang Zheng
Myristicin (MYR) mainly occurs in nutmeg and belongs to alkoxy-substituted allylbenzenes, a class of potentially toxic natural chemicals. RNA interaction with MYR metabolites in vitro and in vivo has been investigated in order to gain a better understanding of MYR toxicities. We detected two guanosine adducts (GA1 and GA2), two adenosine adducts (AA1 and AA2), and two cytosine adducts (CA1 and CA2) by LC-MS/MS analysis of total RNA extracts from cultured primary mouse hepatocytes and liver tissues of mice after exposure to MYR. An order of nucleoside adductions was found to be GAs > AAs > CAs, and the result of density functional theory calculations was in agreement with that detected by the LC-MS/MS-based approach. In vitro and in vivo studies have shown that MYR was oxidized by cytochrome P450 enzymes to 1′-hydroxyl and 3′-hydroxyl metabolites, which were then sulfated by sulfotransferases (SULTs) to form sulfate esters. The resulting sulfates would react with the nucleosides by SN1 and/or SN2 reactions, resulting in RNA adduction. The modification may alter the biochemical properties of RNA and disrupt RNA functions, perhaps partially contributing to the toxicities of MYR.
研究领域:
毒理学
·
药理学
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分子生物学
·
分析化学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2022
·
IF 3.973
Mingyu Zhang,Yaodong Hu,Wei Li,Chen Sun,Chunjing Guan,Ying Peng,Jiang Zheng
2,6-Dimethylphenol (2,6-DMP) is an environmental pollutant found in industrial wastewater. Exposure to 2,6-DMP is of increasing concern as it endangered reportedly some aquatic animals. In this study, we investigated the metabolic activation and hepatotoxicity of 2,6-DMP. 2,6-DMP was metabolized to an o-quinone methide intermediate in vitro and in vivo. The electrophilic metabolite was reactive to the sulfhydryl groups of glutathione, N-acetyl cysteine, and cysteine. NADPH was required for the formation of the reactive metabolite. The quinone methide intermediate reacted with cysteine residues to form hepatic protein adduction. A single dose of 2,6-DMP induced marked elevation of serum ALT and AST in mice. Both the protein adduction and hepatotoxicity of 2,6-DMP showed dose dependency.
研究领域:
毒理学
·
环境科学
·
药理学
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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
·
毒理学
·
药物代谢
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产品关联
DOI
PubMed
高影响因子
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