Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.

Autor: Wang YG; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Gan CP; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Beukers-Korver J; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Rosing H; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Li WL; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Wagenaar E; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Lebre MC; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Song JY; Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, the Netherlands., Pritchard C; Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Bin Ali R; Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Huijbers I; Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands., Beijnen JH; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, 3584 CG, Utrecht, The Netherlands., Schinkel AH; Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. a.schinkel@nki.nl.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Nov 04. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1038/s41401-024-01407-4
Abstrakt: Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2 -/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2 -/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2 -/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2 -/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2 -/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a "healthy" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.
(© 2024. The Author(s).)
Databáze: MEDLINE
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