TOXICOLOGY
·
2022
·
IF 4.571
Yuan Jiang,Lin Qin,Anjing Lu,Juan Chen,Jianmei Wang,Qianru Zhang,Yanliu Lu,Qihai Gong,Jianmei Gao,Hong Ma,Daopeng Tan,Yuqi He
Strychnine is one of the main bioactive and toxic constituents of Semen Strychni. In the present study, the neurotoxic effects of strychnine, and the role of individual differences in metabolism on susceptibility to neurotoxicity of strychnine were investigated. The acute toxicity was observed by a single dose of strychnine (2.92 mg/kg, i.g.) in rats, the epileptic stages of rats were scored according to Racine’s scale. The neurotoxicity of strychnine was evaluated by the levels of ROS , MDA , SOD and GSH in hippocampus, striatum, and cortex tissues measurements and histopathological analysis. The concentrations of strychnine in the plasma, hippocampus, striatum, and cortex tissues were determined using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The expressions of the cytochrome P450 , which is the most critical protein family involved in drugs metabolism, were detected by proteomics . The mechanism of susceptibility to neurotoxicity of strychnine was elucidated by correlation analysis among above indicators. The results indicated that striatum and cortex were the main toxic targets of strychnine, and the CYP3A1 might be a susceptible biomarker to neurotoxicity of strychnine. These results provide valuable insights into the neurotoxic susceptibility of strychnine that will aid in the rational clinical use of strychnine (possibly including Semen Strychni).
研究领域:
药理学
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毒理学
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神经科学
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蛋白质组学
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产品关联
DOI
PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2024
·
IF 2.7
Guofang Bi,Fengting Liang,Ting Wu,Peng Wang,Xiaowen Jiang,Shuang Hu,Chenghua Wu,Wenhong Zhou,Jiayin Guo,Xiao Yang,Jian-hong Fang,Wenying Chen,Huichang Bi
Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2018
·
IF 3.862
Lihui Qiu,Qian Li,Jiangeng Huang,Qi Wu,Kun Tu,Ya Wu,Xin Zhang,Junyi Qian,Ran Zhang,Gao Li,Minghui Sun,Luqin Si
The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG 2k -PCL x polymeric micelles (mPEG 2k -PCL 2k , mPEG 2k -PCL 3.5k , mPEG 2k -PCL 5k and mPEG 2k -PCL 10k ) ranging from 20 to 100 nm were prepared to investigate the inhibitory or inductive activities by in vitro incubations of rat liver microsomes and primary rat hepatocytes. Inhibition of these polymeric micelles on CYP1A2 , CYP2B1 , CYP2C6, CYP2C11 , CYP2D2 and CYP3A1/2 isoenzymes were observed above their critical micelle concentrations (>10 μg·mL −1 ) and in a concentration-dependent manner. The mPEG 2k -PCL 2k micelles showed the strongest inhibition of CYP1A2, followed by CYP2C11. The micelles with lower molecular weight PCL segment exhibited more potent inhibitory potential. Induction on CYP1A2, CYP2B1 and CYP3A1/2 activity (2.1–7.2-fold, 1.5–2.4-fold and 1.3–3.0-fold, respectively) were detected at all tested concentrations (0.1–1000 μg·mL −1 or 0.1–100 μg·mL −1 ). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG 2k -PCL x micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG 2k -PCL x micelles can interfere with the normal metabolic function of CYP450s in vitro , indicating polymeric micelles as promising drug nano-carriers might cause micelle–drug interaction and the in vivo interaction deserves further investigation.
研究领域:
药理学
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毒理学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
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2018
·Vol. 73
·期 6
·329-334
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IF 1.016
Darbalaei Sanaz,Zhang Xinlin,Wang Nanxi,Qin Yanjie,Han Xuemei,Rang Ying,Zhai Xuejia,Lu Yongning
Aprepitant (APT), an antiemetic drug belonging to the class of substance P antagonists is efficiently used in both acute and delayed chemotherapy-induced nausea and vomiting. Nausea and vomiting induced by imatinib (IMA) as a chemotherapeutic drug could be reduced by APT. This study
investigated the effect of APT on the pharmacokinetics of IMA and its major metabolite N-desmethyl imatinib (N-D IMA) in rats and the mechanism of this drug-drug interaction. The results indicated that after 3 days of pretreatment with APT (10 mg/kg), the blood concentration of IMA was decreased
in both of oral and intravenous routes of IMA administration compared to vehicle treated rats, whereas the blood concentration of N-D IMA was not significantly changed. The total clearance (CL/F) of oral and intravenous given IMA was increased by 1.41 and 1.32-fold, and the bioavailability
was greatly decreased about 30.43% and 24.40% respectively. At this time, the P-gp and the hepatic CYP3A1 were increased at both the mRNA and protein levels. These results demonstrated that ingestion of APT will decrease the bioavailability of IMA to a significant extent in rats and the drug-drug
interaction between APT and IMA appears to be due to modulation of P-gp and CYP3A1.
研究领域:
药理学
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肿瘤学
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药学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Mengni Shu,Guoyong Jiang,Chunchao Nie,Yi Chen
Pre-laboratory studies demonstrate that polysaccharide from Ganoderma atrum (PSG-1) exerts a protective effect against acrylamide (AA)-induced liver injury in rats. However, the mechanism underlying PSG-1-mediated hepatoprotection remains unclear. Herein, we employed an integrated metabolomics and proteomics approach to elucidate the molecular mechanisms of AA-induced liver injury using an in vivo rat model. Consequently, our analysis revealed that two key metabolic pathways—namely, arachidonic acid metabolism and retinol metabolism—mediate the protective effects of PSG-1. Furthermore, Phenylalanyl-Threonine, L-cis-Cyclo (aspartylphenylalanyl), bilirubin, and palmitic amide could serve as potential biomarkers for AA-induced liver injury, and the hepatoprotective effects of PSG-1 were mediated via target proteins Cyp3a1, Cyp2c7, Alox15, and Adh6. These findings elucidate the molecular mechanisms underlying PSG-1-mediated hepatoprotection and establish a framework for deciphering the therapeutic mechanisms by which functional foods counteract dietary toxicants.
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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生物化学
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营养科学
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功能食品
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系统生物学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）