Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

Author:

Albadry Mohamed,Höpfl Sebastian,Ehteshamzad Nadia,König Matthias,Böttcher Michael,Neumann Jasna,Lupp Amelie,Dirsch Olaf,Radde Nicole,Christ Bruno,Christ Madlen,Schwen Lars Ole,Laue Hendrik,Klopfleisch Robert,Dahmen UtaORCID

Abstract

AbstractLittle 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.

Funder

German Research Foundation (DFG), SteaPKMod

German Research Foundation (DFG), QuaLiPerF

Federal Ministry of Education and Research

German Research Foundation (DFG), SimLivA

Universitätsklinikum Jena

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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