Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism.

Autor: Albadry M; Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany.; Department of Pathology, Faculty of Veterinary Medicine, Menoufia University, Shebin Elkom, Menoufia, Egypt., Höpfl S; Institute for Systems Theory and Automatic Control, Faculty of Engineering Design, Production Engineering and Automotive Engineering, University of Stuttgart, Stuttgart, Germany., Ehteshamzad N; Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany., König M; Institute for Theoretical Biology, Institute of Biology, Humboldt-University, Berlin, Germany., Böttcher M; MVZ Medizinische Labore Dessau Kassel GmbH, Bauhüttenstraße 6, 06847, Dessau-Roßlau, Germany., Neumann J; MVZ Medizinische Labore Dessau Kassel GmbH, Bauhüttenstraße 6, 06847, Dessau-Roßlau, Germany., Lupp A; Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany., Dirsch O; Institute of Pathology, Klinikum Chemnitz, Chemnitz, Germany., Radde N; Institute for Systems Theory and Automatic Control, Faculty of Engineering Design, Production Engineering and Automotive Engineering, University of Stuttgart, Stuttgart, Germany., Christ B; Cell Transplantation/Molecular Hepatology Lab, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany., Christ M; Cell Transplantation/Molecular Hepatology Lab, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany., Schwen LO; Fraunhofer MEVIS, Max-Von-Laue-Str. 2, 28359, Bremen, Germany., Laue H; Fraunhofer MEVIS, Max-Von-Laue-Str. 2, 28359, Bremen, Germany., Klopfleisch R; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany., Dahmen U; Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany. Uta.Dahmen@med.uni-jena.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Dec 17; Vol. 12 (1), pp. 21825. Date of Electronic Publication: 2022 Dec 17.
DOI: 10.1038/s41598-022-26483-6
Abstrakt: Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms.
(© 2022. The Author(s).)
Databáze: MEDLINE
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