CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Wenwen Luo,Keqi Hu,Yijing Chen,Lin Wang,Yungang Liu
Tris(2-butoxyethyl) phosphate (TBOEP) is an organophosphorus flame retardant ubiquitously present in the environment and even the human body. TBOEP is toxic in multiple tissues, which forms dealkylated and hydroxylated metabolites under incubation with human hepatic microsomes; however, the impact of TBOEP metabolism on its toxicity, particularly mutagenicity (typically requiring metabolic activation), is left unidentified. In this study, the mutagenicity of TBOEP in human hepatoma cell lines (HepG2 and C3A) and the role of specific CYPs were studied. Through molecular docking, TBOEP bound to human CYP1A1, 1B1, 2B6 and 3A4 with energies and conformations favorable for catalyzing reactions, while the conformations of its binding with human CYP1A2 and 2E1 appeared unfavorable. In C3A cells (endogenous CYPs being substantial), TBOEP exposing for 72 h (2-cell cycle) at low micromolar levels induced micronucleus, which was abolished by 1-aminobenzotriazole (inhibitor of CYPs); in HepG2 cells (CYPs being insufficient) TBOEP did not induce micronucleus, whose effect was however potentiated by pretreating the cells with PCB126 (CYP1A1 inducer) or rifampicin (CYP3A4 inducer). TBOEP induced micronucleus in Chinese hamster V79-derived cell lines genetically engineered for stably expressing human CYP1A1 and 3A4, but not in cells expressing the other CYPs. In C3A cells, TBOEP selectively induced centromere protein B-free micronucleus (visualized by immunofluorescence) and PIG-A gene mutations, and elevated γ-H2AX rather than p-H3 (by Western blot) which indicated specific double-strand DNA breaks. Therefore, this study suggests that TBOEP may induce DNA/chromosome breaks and gene mutations in human cells, which requires metabolic activation by CYPs, primarily CYP1A1 and 3A4.
研究领域:
毒理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
·
2025
·Vol. 13
·期 3
·e70127
·
IF 2.3
Hang Yang,Shuanghu Wang,Quan Zhou,Peiwu Geng,Zebei Lu,Qinrong Lin,Chunhong Chen,Yunfang Zhou,Jianping Cai,Dapeng Dai
Tofacitinib is a widely used medication for the treatment of arthritis. It has been reported that some patients experience abnormal cholesterol levels following treatment, leading to recommendations for the coadministration of lipid-lowering drugs such as statins. In this study, we investigated the potential drug–drug interactions between tofacitinib and the statins simvastatin and lovastatin. In the in vitro experiments, rat liver microsomes were employed to evaluate the inhibitory effects of lipid-lowering agents on the metabolism of tofacitinib, with the primary metabolite M8 analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. The results showed that simvastatin and lovastatin significantly inhibited the metabolism of tofacitinib, with IC 50 values of 5.837 and 10.68 μM, respectively. For the in vivo pharmacokinetic studies, Sprague–Dawley rats were pretreated with simvastatin or lovastatin via oral gavage for 7 days before the oral gavage of tofacitinib. This pretreatment led to an increased area under the concentration–time curve of tofacitinib, suggesting that a potential reduction in the first metabolism and/or systemic clearance takes place. These findings demonstrate significant interactions between tofacitinib and certain lipid-lowering agents in the rat model, particularly simvastatin and lovastatin, both in vitro and in vivo.
研究领域:
药理学
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临床医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
REGULATORY TOXICOLOGY AND PHARMACOLOGY
·
2020
·
IF 2.652
Han Luo,Yuan Xu,Dongyi Sun,Yi Cheng,Zhenliang Sun,Jing Gao,Yuanjin Zhang,Xin Wang
Paris saponins , also known as polyphyllins, are natural compounds extracted from Paris polyphylla , which have many pharmacological activities , such as anti-inflammation and anti-cancer. In particular, paris saponin I, II, VII and polyphyllin VI are the components of the quality standard for Paris polyphylla . However, the inhibition risk of polyphyllins on cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGT) remains unclear. Therefore, this report investigated the potential inhibitory effects of paris saponin I, II, VII and polyphyllin VI on the activities of CYP (CYP1A2, CYP2B1, CYP2C11 , CYP2D1 , CYP2E1 and CYP3A2) and UGT (UGT1A1, UGT1A3, UGT1A6, PROG and AZTG) through cocktail inhibition assays in vitro . In the study of CYP, polyphyllin VI exhibited weak inhibition on CYP2D1 activity in rat liver microsomes with IC 50 value at 45.2 μM, while paris saponin VII weakly inhibited CYP2C11 and CYP2E1 activities with IC 50 value at 42.0 and 67.7 μM, respectively. In the study of UGT, none of the four steroidal saponins showed significant inhibition risk. In conclusion, paris saponin I, II, VII and polyphyllin VI have very low potential to cause the possible toxicity and drug interactions involving CYP and UGT enzymes, indicating that they are safe enough to take with drugs.
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
ENVIRONMENTAL POLLUTION
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2017
·
IF 5.099
Zheng-Hai Du,Jun Xia,Xiao-Chen Sun,Xue-Nan Li,Cong Zhang,Hua-Shan Zhao,Shi-Yong Zhu,Jin-Long Li
Di-(2-ethylhexyl)-phthalate (DEHP) is causing serious health hazard in wildlife animal and human through environment and food chain, including the effect of brain development and impacted neurobehavioral outcomes. However, DEHP exposure caused cerebellar toxicity in bird remains unclear. To evaluate DEHP-exerted potential neurotoxicity in cerebellum, male quails were exposed with 0, 250, 500 and 750 mg/kg BW/day DEHP by gavage treatment for 45 days. Neurobehavioral abnormality and cerebellar histopathological alternation were observed in DEHP-induced quails. DEHP exposure increased the contents of total Cytochrome P450s (CYPs) and Cytochrome b5 (Cyt b5) and the activities of NADPH-cytochrome c reductase (NCR) and aniline-4-hydeoxylase (AH) in quail cerebellum. The expression of nuclear xenobiotic receptors (NXRs) and the transcriptions of CYP enzyme isoforms were also influenced in cerebellum by DEHP exposure. These results suggested that DEHP exposure caused the toxic effects of quail cerebellum. DEHP exposure disrupted the cerebellar CYP enzyme system homeostasis via affecting the transcription of CYP enzyme isoforms. The cerebellar P450arom and CYP3A4 might be biomarkers in evaluating the neurotoxicity of DEHP in bird. Finally, this study provided new evidence that DEHP-induced toxic effect of quail cerebellum was associated with activating the NXRs responses and disrupting the CYP enzyme system homeostasis.
研究领域:
环境毒理学
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神经毒理学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2021
·
IF 4.36
Yuanyuan Chai,Yunxia Xu,Ziyin Xia,Xin Huang,Luyong Zhang,Zhenzhou Jiang
Ethnopharmacological relevance Zhuanggu Guanjie Pill (ZGGJP), a modern Chinese medicine formula, is composed of 12 herbs and has been used to treat osteoporosis in China for almost 30 years. However, no in vivo study of the influences of ZGGJP on the cytochrome P450 (CYP) activities have been reported. Aim of the study The aim of this study was to evaluate the effects of ZGGJP on the activities and the mRNA expression of CYP enzymes (CYP1A2, CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 and CYP3A) and their corresponding nuclear receptor levels in rats. Materials and methods After 7 days oral treatment of ZGGJP at low- and high-dose, cocktail solution was given to rats. Blood samples were collected at series of time points. The plasma concentrations of probe drugs and their corresponding metabolites were determined by UPLC-MS/MS. The influence of ZGGJP on the activities of seven CYPs were evaluated the metabolic ratios (C max and AUC 0-t) for metabolites/probe drugs. In addition, the effects of ZGGJP on the mRNA expression of CYPs and their corresponding nuclear receptors in rat liver were evaluated by real-time PCR. Results ZGGJP showed significant inductive effects on CYP1A2 and CYP2B6 of both male and female rats. The influence of ZGGJP on CYP2C9 and CYP3A showed gender difference. ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but have no influence on the activities in male rats. ZGGJP had no effects on CYP2D6, CYP2C19 and CYP2E1. The mRNA expression results of CYPs were in accordance with the pharmacokinetic results. The mRNA expression levels of constitutive androstane receptor (CAR) and vitamin D receptor (VDR) were increased significantly in female rats at high dosage, but no significant changes were observed in male rats. Conclusion ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.
研究领域:
民族药理学
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药物代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2020
·Vol. 15
·期 1
·1-18
·
IF 2.96
Qin Zifei,Jia Mengmeng,Yang Jing,Xing Han,Yin Zhao,Yao Zhihong,Zhang Xiaojian,Yao Xinsheng
Background Kang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug–drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear.Methods PK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC–MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme.Results After dosing, 9 alkaloids were found with Cmax and t1/2 values of 0.17–422.70 μmol/L and 1.78–4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 values of 0.63–7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma values of 12.35% and 60.23–87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki no more than 0.1.Conclusion sWe summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.
研究领域:
药理学
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药剂学
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药物代谢
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毒理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2021
·
IF 8.128
Changping Yang,Zhongwei Jiang,Qing Wu,Congyi Hu,Chengzhi Huang,Yuanfang Li,Shujun Zhen
Although a number of nanozymes have been developed, it is still difficult to develop single-component nanozyme with overall high multienzyme-like activities. In this study, the nanosized metal–organic frameworks (nano-MOFs) FePCN (PCN stands for porous coordination network) was synthesized by integrating zirconium and iron ions with different catalytic property on single-component MOFs and exhibited superior intrinsic multienzyme-like activities, namely oxidase-, peroxidase- and phosphatase-mimicking activity. The catalytic active sites of oxidase- and peroxidase-, and phosphatase-like activity of FePCN were Fe-centers and Zr-O clusters, respectively. Based on the intrinsic oxidase-like activity and the similarity of molecular structures between cytochrome P450 oxidase (CYP) cofactors and the organic linker in FePCN, FePCN exhibited high CYP-like activity to catalyze the oxidation of hypotensive drug 1,4-dihydropyridine (1,4-DHP) into diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (DDPD) and the yield of DDPD reached over 80%. Moreover, as peroxidase- and phosphatase-mimics, FePCN was successfully applied to detecting H 2 O 2 under neutral condition and catalyzing the dephosphorylation of adenosine triphosphate (ATP), respectively. This study provides a feasible way for rational design one-component nanomaterials as multienzyme-mimics.
研究领域:
纳米技术
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材料科学
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生物化学
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药物化学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Shuaishuai Chen,Weiyu Guo,Huan Liu,Jiang Zheng,Dingyan Lu,Jia Sun,Chun Li,Chunhua Liu,Yonglin Wang,Yong Huang,Wen Liu,Yongjun Li,Ting Liu
Psoralen and isopsoralen are the major components responsible for Psoraleae Fructus-induced hepatotoxicity. This study explored the role of metabolic activation by cytochrome P450 (CYP) enzymes in psoralen- and isopsoralen-induced cytotoxicity and its potential mechanisms. Inhibitors of CYP1A2 , 2C9, 2C19, 2D6, 2E1, and 3A4 were used to screen specific CYP enzymes responsible for the metabolic activation of psoralen and isopsoralen in mouse primary hepatocytes, which was verified using the corresponding transfected cell lines. Network toxicology and transcriptome analyses were performed to explore the mechanisms underlying toxicity. Psoralen and isopsoralen decreased the viability of mouse primary hepatocytes, whereas the inhibition of CYP2C9 , 2C19, 2D6, and 2E1 significantly increased their viability. Psoralen-induced cytotoxicity was significantly enhanced by the overexpression of CYP2C19 in Chinese hamster ovary cells, whereas the overexpression of the above CYP enzymes did not affect the cytotoxicity of isopsoralen. Psoralen- and isopsoralen-induced cytotoxic effects were associated with putative core targets (i.e., Fn1 , Thbs1 , and Tlr2) and multiple signaling pathways (e.g., PI3K-Akt, MAPK , and TNF pathways). Our results demonstrate that the metabolic activation of psoralen and isopsoralen is mediated by CYP enzymes, thereby regulating multiple core targets and signaling pathways and resulting in cytotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Chaofeng Xing,Minyi Tang,Jianqin Yang,Shuai Wang,Qihua Xu,Wenbin Feng,Yunping Mu,Fanghong Li,Allan Zijian Zhao
Type 1 diabetes mellitus (T1DM) is characterized by life-threatening absolute insulin deficiency . Although ω-3 polyunsaturated fatty acids (PUFAs) displayed significant anti-hyperglycemic activity, the insulinotropic effects of their metabolites remain unknown. In this study, we took advantage of a transgenic model , mfat-1, that overexpresses an ω-3 desaturase and can convert ω-6 PUFAs to ω-3 PUFAs. Eicosapentaenoic acid (EPA) was sharply elevated in the pancreatic tissues of mfat-1 transgenic mice compared with wild-type (WT) mice. In contrast to the WT mice, the mfat-1 transgenics did not develop overt diabetes and still maintained normal blood glucose levels and insulin secretion following streptozotocin-treatment. Furthermore, under the condition of pancreatic β-cell damage, co-incubation of the metabolites of EPA produced from the CYP 450 pathway with isolated islets promoted the overexpression of insulin as well as β-cell specific markers, pdx1 and Nkx6.1 in pancreatic α-cells. Addition of EPA metabolites to the cultured glucagon-positive α-cell lines, a series of pancreatic β-cell markers were also found significantly elevated. Combined together, these results demonstrated the effects of ω-3 PUFAs and their metabolites on the trans-differentiation from α-cells to β-cells and its potential usage in the intervention of T1DM.
研究领域:
内分泌学
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糖尿病研究
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR GENETICS AND GENOMICS
·
2022
·Vol. 297
·期 3
·801-815
·
IF 2.98
Zhang Yonglei,Gao Shanshan,Zhang Ping,Sun Haidi,Lu Ruixue,Yu Runnan,Li Yanxiao,Zhang Kunpeng,Li Bin
Eugenol, a plant-derived component possessing small side effects, has an insecticidal activity to Tribolium castaneum ; however, the underlying molecular mechanisms of eugenol acting on T. castaneum are currently unclear. Here, a nerve conduction carboxylesterase and a detoxifying glutathione S-transferase were significantly inhibited after eugenol exposure, resulting in the paralysis or death of beetles. Then, RNA-sequencing of eugenol-exposed and control samples identified 362 differentially expressed genes (DEGs), containing 206 up-regulated and 156 down-regulated genes. RNA-seq data were validated further by qRT-PCR. GO analysis revealed that DEGs were associated with 1308 GO terms of which the most enriched GO terms were catalytic activity, and integral component of membrane; KEGG pathway analysis showed that these DEGs were distributed in 151 different pathways, of which some pathways associated with metabolism of xenobiotics or drug were significantly enriched, which indicated that eugenol most likely disturbed the processes of metabolism, and detoxication. Moreover, several DEGs including Hexokinase type 2 , Isocitrate dehydrogenase , and Cytochrome b-related protein , might participate in the respiratory metabolism of eugenol-exposed beetles. Some DEGs encoding CYP , UGT , GST , OBP , CSP , and ABC transporter were involved in the xenobiotic or drug metabolism pathway, which suggested that these genes of T. castaneum participated in the response to eugenol exposure. Additionally, TcOBPC11/ TcGSTs7 , detected by qRT-PCR and RNA-interference against these genes, significantly increased the mortality of eugenol-treated T. castaneum , providing further evidence for the involvement of OBP/GST in eugenol metabolic detoxification in T. castaneum . These results aid eugenol insecticidal mechanisms and provide the basis of insect control.
研究领域:
昆虫学
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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
危险品化学品经营许可证（带存储）