Hanbing Jiang, Jie Yang, Yucui Hou, Ke Zhang, Yi Ren, Jing Huang, Huanhuan Li, Tongji Cai, Zhonghua Ouyang, Jia Zhao, Peng Yu
{"title":"基于叶酸聚谷氨酸合成酶和γ -谷氨酰水解酶表达的肝细胞和胚胎肾细胞内甲氨蝶呤代谢评价。","authors":"Hanbing Jiang, Jie Yang, Yucui Hou, Ke Zhang, Yi Ren, Jing Huang, Huanhuan Li, Tongji Cai, Zhonghua Ouyang, Jia Zhao, Peng Yu","doi":"10.2174/1389200224666230406120714","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Methotrexate (MTX) is a common folic acid antagonist in clinical medicine, easily inducing a common adverse side effect of liver and kidney injury. It has been found that the expression of Folylpolyglutamate Synthetase (FPGS) and gamma-Glutamyl Hydrolase (GGH) may be closely related to that of related proteins to affect the intracellular metabolism of MTX.</p><p><strong>Objective: </strong>The relationship between FPGS/GGH and MTXPGs accumulation in liver and kidney cells was explored by adjusting the expression of FPGS and GGH in cells using UPLC-MS/MS quantitative technology.</p><p><strong>Method: </strong>Based on UPLC-MS/MS quantitative techniques, the relationship between MTXPGs accumulation and FPGS/GGH in hepatocytes and embryonic kidney cells was explored by adjusting the expression of FPGS and GGH, and the effect of FPGS/GGH on the intracellular toxicity of MTX was comprehensively analyzed.</p><p><strong>Result: </strong>The results showed that the difference in methotrexate polyglutamates (MTXPGs) accumulation in liver and kidney cells was related to the difference in FPGS and GGH expression. The expression of FPGS interacted with that of GGH. These results suggest that the protein abundance ratio of FPGS to GGH (FPGS/GGH) has more potential to be used as a predictor of MTX efficacy than the FPGS or GGH single protein index. This can effectively avoid liver and kidney damage caused by MTX and guides the rational use of drugs in MTX.</p><p><strong>Conclusion: </strong>The results prove that there is a positive correlation between the FPGS/GGH and the accumulation of MTXPGS in liver and kidney cells. Summarily, the FPGS/GGH is expected to be a predictor for MTXPGs accumulation and provides an effective method to evaluate the toxicity caused by MTX.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of Intracellular Metabolism of Methotrexate in Hepatocytes and Embryonic Kidney Cells based on Folylpolyglutamate Synthetase and Gamma-Glutamyl Hydrolase Expression.\",\"authors\":\"Hanbing Jiang, Jie Yang, Yucui Hou, Ke Zhang, Yi Ren, Jing Huang, Huanhuan Li, Tongji Cai, Zhonghua Ouyang, Jia Zhao, Peng Yu\",\"doi\":\"10.2174/1389200224666230406120714\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Methotrexate (MTX) is a common folic acid antagonist in clinical medicine, easily inducing a common adverse side effect of liver and kidney injury. It has been found that the expression of Folylpolyglutamate Synthetase (FPGS) and gamma-Glutamyl Hydrolase (GGH) may be closely related to that of related proteins to affect the intracellular metabolism of MTX.</p><p><strong>Objective: </strong>The relationship between FPGS/GGH and MTXPGs accumulation in liver and kidney cells was explored by adjusting the expression of FPGS and GGH in cells using UPLC-MS/MS quantitative technology.</p><p><strong>Method: </strong>Based on UPLC-MS/MS quantitative techniques, the relationship between MTXPGs accumulation and FPGS/GGH in hepatocytes and embryonic kidney cells was explored by adjusting the expression of FPGS and GGH, and the effect of FPGS/GGH on the intracellular toxicity of MTX was comprehensively analyzed.</p><p><strong>Result: </strong>The results showed that the difference in methotrexate polyglutamates (MTXPGs) accumulation in liver and kidney cells was related to the difference in FPGS and GGH expression. The expression of FPGS interacted with that of GGH. These results suggest that the protein abundance ratio of FPGS to GGH (FPGS/GGH) has more potential to be used as a predictor of MTX efficacy than the FPGS or GGH single protein index. This can effectively avoid liver and kidney damage caused by MTX and guides the rational use of drugs in MTX.</p><p><strong>Conclusion: </strong>The results prove that there is a positive correlation between the FPGS/GGH and the accumulation of MTXPGS in liver and kidney cells. Summarily, the FPGS/GGH is expected to be a predictor for MTXPGs accumulation and provides an effective method to evaluate the toxicity caused by MTX.</p>\",\"PeriodicalId\":10770,\"journal\":{\"name\":\"Current drug metabolism\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current drug metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1389200224666230406120714\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1389200224666230406120714","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Evaluation of Intracellular Metabolism of Methotrexate in Hepatocytes and Embryonic Kidney Cells based on Folylpolyglutamate Synthetase and Gamma-Glutamyl Hydrolase Expression.
Background: Methotrexate (MTX) is a common folic acid antagonist in clinical medicine, easily inducing a common adverse side effect of liver and kidney injury. It has been found that the expression of Folylpolyglutamate Synthetase (FPGS) and gamma-Glutamyl Hydrolase (GGH) may be closely related to that of related proteins to affect the intracellular metabolism of MTX.
Objective: The relationship between FPGS/GGH and MTXPGs accumulation in liver and kidney cells was explored by adjusting the expression of FPGS and GGH in cells using UPLC-MS/MS quantitative technology.
Method: Based on UPLC-MS/MS quantitative techniques, the relationship between MTXPGs accumulation and FPGS/GGH in hepatocytes and embryonic kidney cells was explored by adjusting the expression of FPGS and GGH, and the effect of FPGS/GGH on the intracellular toxicity of MTX was comprehensively analyzed.
Result: The results showed that the difference in methotrexate polyglutamates (MTXPGs) accumulation in liver and kidney cells was related to the difference in FPGS and GGH expression. The expression of FPGS interacted with that of GGH. These results suggest that the protein abundance ratio of FPGS to GGH (FPGS/GGH) has more potential to be used as a predictor of MTX efficacy than the FPGS or GGH single protein index. This can effectively avoid liver and kidney damage caused by MTX and guides the rational use of drugs in MTX.
Conclusion: The results prove that there is a positive correlation between the FPGS/GGH and the accumulation of MTXPGS in liver and kidney cells. Summarily, the FPGS/GGH is expected to be a predictor for MTXPGs accumulation and provides an effective method to evaluate the toxicity caused by MTX.
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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