Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

        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.


DOI: 10.1038/s41598-022-26483-6

Projects: SteaPKMod

Publication type: Journal

Journal: Scientific Reports

Citation: Sci Rep 12(1),21825

Date Published: 1st Dec 2022

Registered Mode: by DOI

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

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Albadry, M., Höpfl, S., Ehteshamzad, N., König, M., Böttcher, M., Neumann, J., Lupp, A., Dirsch, O., Radde, N., Christ, B., Christ, M., Schwen, L. O., Laue, H., Klopfleisch, R., & Dahmen, U. (2022). Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism. In Scientific Reports (Vol. 12, Issue 1). Springer Science and Business Media LLC.

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Created: 17th Dec 2022 at 20:34

Last updated: 17th Dec 2022 at 20:40

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