SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Chanlin Fang,Yundong Yu,Shanshan Di,Xinquan Wang,Yuanxiang Jin
The tire antioxidant 6PPD has garnered extensive attention due to its widespread presence in the environment and the harmful effects of its transformation products on aquatic organisms. 6PPD has been detected in airborne dust, and it can enter mammals through inhalation exposure. While the toxic effects of 6PPD exposure have been reported in mammals, its effects on hepatic metabolism still remain poorly understood. Here, we collected the serum and liver samples at 1, 6, and 72 h following a single oral exposure of 100 mg/kg body weight (bw) 6PPD, respectively. We also investigated changes in serum and hepatic physiological indicators and metabolites, correspondingly. Results indicated that single time oral exposure a high dose of 6PPD did not significantly affect the physiological indexes of rats within a short time frame. However, untargeted metabolomics analysis of the metabolites in the liver at 1, 6, and 72 h revealed that the number of differential expression metabolites gradually increased over time and the most affected substances were lipids and lipid-like molecules. Interestingly, the KEGG pathway enrichment analysis indicated that 6PPD disrupted the riboflavin metabolism, leading to a significant decrease in FMN levels at all time points. In addition, the hepatic glucose metabolism was significantly affected at 6 and 72 h after oral administration. Taken together, short-term exposure to 6PPD disturbed lipid and riboflavin metabolism and gradually affected glucose metabolism in the liver of rats. These findings revealed the impacts of 6PPD on the hepatic metabolism in animals, and also offered some important insights into its toxicology and health risk.
研究领域:
毒理学
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环境科学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
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2012
·Vol. 67
·期 9
·804-808
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IF 1.006
Liu Xiao-You,Fang Zhong-Ze,Dong Pei-Pei,Shi Xiang-Hua,Sun Xu-Yong,Teng Yan-Jie
The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system
was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly
inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters
(Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 M for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs.
研究领域:
药理学
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生物化学
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临床医学
✓ 已验证
DOI
高影响因子
Environmental Science-Nano
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2025
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IF 5.1
Shuoli Ma,Wen-Xiong Wang
The toxicity of environmental pollutants is often manifested through metabolic disruptions and damage to detoxification organs. However, current understanding is insufficient to explain the physiological response mechanisms of metabolically abnormal fish exposed to secondary pollutants in complex natural environments. This study established a fish model with non-alcoholic fatty liver to evaluate the effects of Zn oxide nanoparticles (nZnO) and Zn²⁺ on physiological metabolism using untargeted lipidomics and bioimaging techniques. Nile red and hematoxylin and eosin (H&E) staining indicated that increased Zn levels reduced the number of lipid droplets (LDs) and hepatocyte vacuolization in the livers of groupers. Non-targeted lipidomics, employing an unsupervised K-means clustering algorithm, identified key lipid profiles that differentiated the effects of nZnO and Zn, including TG (16:0/16:1/18:1), PC (18:2/22:6), TG (18:2/18:2/22:6), SM (d18:1/24:1), and TG (16:1/18:1/18:2). The increased content of SM (d18:1/24:0) indicated that fish liver cells internalized nZnO via lipid raft structures on the cell membrane, a process distinct from Zn ion uptake. Moreover, nZnO/Zn treatments significantly activated lipolysis regulation in fish liver experiencing oxidative stress. This study contributed to the use of non-targeted lipidomics to identify differential biomarkers of nZnO and Zn, as well as their compensatory mechanisms in metabolically abnormal fish. These findings provide novel insights into the effects of nanometal exposure on aquatic animal health in complex environments.
研究领域:
环境毒理学
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代谢组学
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水生生物学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Veterinary Science
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2025
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IF 2.9
Jianping Liang,Can Cui,Wenge Ren,Linglin Li,Linyi Lv,Xianhui Huang,Xiangmei Li
Introduction Tenvermectin (TVM) is a novel avermectin-class drug that has attracted attention for its superior antiparasitic potency, low toxicity, and broad-spectrum activity. However, uncertainty about its interaction with cytochrome P450 enzymes (CYPs) has raised concerns about potential therapeutic failure, increased risk of toxicity, dangerous drug combinations, and prolonged discontinuation periods. Method To address these critical safety concerns, we conducted a systematic comparative study using a highly selective and quantitatively accurate substrate conversion assay to assess and compare the effects of TVM and ivermectin (IVM) on the activities of key CYPs (CYP1A1/2, 2B1, 2C6, 2D2, and 3A1/2). Results TVM induced CYP1A, 2C, 2D and 3A activities only at high therapeutic doses (2.5 mg/kg), and its induction was significantly weaker than that of IVM at all doses tested, with the most pronounced difference for CYP3A1/2. Although TVM had weak inhibitory effects on CYP2B1 and 2D2, at therapeutic concentrations these effects are presumably unlikely to cause clinically significant CYP-mediated drug interactions. Conclusion As the first study to report the effects of TVM on CYP enzyme activity, these findings provide important experimental evidence and a theoretical framework for its clinical safety assessment, development of optimal dosing regimens, and rational polypharmacy strategies.
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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临床药理学
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寄生虫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2020
·
IF 4.96
Hongwei Yao,Jingkai Gu,Yuqin Shan,Yani Wang,Xue Chen,Dong Sun,Yingjie Guo
Patients with diabetic mellitus tend to have a poor response to clopidogrel (Clop) due to reduced generation of active metabolite (Clop-AM). However, the underlying mechanism is not elucidated. A type 2 diabetic mellitus (T2DM) rat model was established by combining high-fat diet feeding and low-dose streptozotocin (STZ) injection. The reduced Clop-AM exposure was observed in T2DM rats after oral administration of Clop. However, in vitro liver microsomes incubated with Clop exhibited increased Clop-AM levels in T2DM rats due to a significant decrease in carboxylesterase (CES)1 expression and activity and a significant increase in the expression or activity of CYP1A2 and CYP3A . Interestingly, different from oral administration, the significantly increased C max of Clop-AM was observed in T2DM rats after intravenous injection, with no difference in AUC 0-t and t 1/2 values between the two strains. Meanwhile, in situ single -pass intestinal perfusion study showed lower absorption rate constant ( K a) and effective apparent permeability values ( P eff ) of Clop in T2DM rats than in control rats. It is explained by the increased expression or function of P-glycoprotein (P-gp) and pregnane X receptor (PXR) in duodenum and jejunum of T2DM rats. Moreover, the decreased Clop-AM level in T2DM rats was eliminated by the pretreatment of cyclosporin A , a P-gp inhibitor. It suggests that intestinal absorption, not hepatic metabolism is responsible for the reduced Clop-AM exposure in T2DM rats. P-gp might be the key factor causing the reduction of Clop absorption, consequently making less Clop available for Clop-AM formation.
研究领域:
药理学
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糖尿病研究
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药学
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代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Yingying Zhang,Yun Pan,Xiangyu Bai,Wen Sun,Xingfan Zhou,Qing Dong,Hui Wang,Yuanbao Zhang,Wenlin Bai,Wenping Zhang
Epidemiological evidence on the health effects of pesticide exposure among greenhouse workers is limited, and the mechanisms are lacking. Building upon our team’s previous population study, we selected two pesticides, CPF and EB, with high detection rates, based on the theoretical foundation that the liver serves as a detoxifying organ, we constructed a toxicity model using HepG2 cells to investigate the impact of individual or combined pesticide exposure on the hepatic metabolism profile, attempting to identify targeted biomarkers. Our results showed that CPF and EB could significantly affect the survival rate of HepG2 cells and disrupt their metabolic profile. There were 117 metabolites interfered by CPF exposure, which mainly affected ABC transporter, biosynthesis of amino acids, center carbon metabolism in cancer, fatty acid biosynthesis and other pathways, 95 metabolites interfered by EB exposure, which mainly affected center carbon metabolism in cancer, HIF-1 signaling pathway, valine, leucine and isoleucine biosynthesis, fatty acid biosynthesis and other pathways. The cross analysis and further biological experiments confirmed that CPF and EB pesticide exposure may affect the HIF-1 signaling pathway and valine, leucine and isoleucine biosynthesis in HepG2 cells, providing reliable experimental evidence for the prevention and treatment of liver damage in greenhouse workers.
研究领域:
毒理学
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细胞生物学
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代谢组学
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环境健康
✓ 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）