دورية أكاديمية
Human Carboxylesterase 1A Plays a Predominant Role in Hydrolysis of the Anti-Dyslipidemia Agent Fenofibrate in Humans.
| العنوان: | Human Carboxylesterase 1A Plays a Predominant Role in Hydrolysis of the Anti-Dyslipidemia Agent Fenofibrate in Humans. |
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| المؤلفون: | Li HX; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Sun MR; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Zhang Y; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Song LL; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Zhang F; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Song YQ; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Hou XD; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)., Ge GB; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.) geguangbo@shutcm.edu.cn. |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Nov; Vol. 51 (11), pp. 1490-1498. Date of Electronic Publication: 2023 Aug 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مستخلص: | Fenofibrate, a marketed peroxisome proliferator-activated receptor- α (PPAR α ) agonist, has been widely used for treating severe hypertriglyceridemia and mixed dyslipidemia. As a canonical prodrug, fenofibrate can be rapidly hydrolyzed to release the active metabolite (fenofibric acid) in vivo, but the crucial enzyme(s) responsible for fenofibrate hydrolysis and the related hydrolytic kinetics have not been well-investigated. This study aimed to assign the key organs and crucial enzymes involved in fenofibrate hydrolysis in humans, as well as reveal the impact of fenofibrate hydrolysis on its non-PPAR-mediated biologic activities. Our results demonstrated that fenofibrate could be rapidly hydrolyzed in the preparations from both human liver and lung to release fenofibric acid. Reaction phenotyping assays coupling with chemical inhibition assays showed that human carboxylesterase 1A (hCES1A) played a predominant role in fenofibrate hydrolysis in human liver and lung, while human carboxylesterase 2A (hCES2A) and human monoacylglycerol esterase (hMAGL) contributed to a very lesser extent. Kinetic analyses showed that fenofibrate could be rapidly hydrolyzed by hCES1A in human liver preparations, while the inherent clearance of hCES1A-catalyzed fenofibrate hydrolysis is much higher (>200-fold) than than that of hCES2A or hMAGL. Biologic assays demonstrated that both fenofibrate and fenofibric acid showed very closed Nrf2 agonist effects, but fenofibrate hydrolysis strongly weakens its inhibitory effects against both hCES2A and hNtoum. Collectively, our findings reveal that the liver is the major organ and hCES1A is the predominant enzyme-catalyzing fenofibrate hydrolysis in humans, while fenofibrate hydrolysis significantly reduces inhibitory effects of fenofibrate against serine hydrolases. SIGNIFICANCE STATEMENT: Fenofibrate can be completely converted to fenofibric acid in humans and subsequently exert its pharmacological effects, but the hydrolytic pathways of fenofibrate in humans have not been well-investigated. This study reported that the liver was the predominant organ and human carboxylesterase 1A was the crucial enzyme involved in fenofibrate hydrolysis in humans. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.) |
| تواريخ الأحداث: | Date Created: 20230807 Latest Revision: 20231012 |
| رمز التحديث: | 20231013 |
| DOI: | 10.1124/dmd.123.001365 |
| PMID: | 37550069 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.123.001365 |