Publikationsdatenbank

Impact of Steatosis on Drug Metabolism of the Liver: Functional and Translational Implications (2024)

Art

Hochschulschrift

Autor

Albadry, Mohamed Awad Mohamed (WE 12)

Quelle

Berlin, 2024 — XII, 134 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/43918

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Background: It was recently reported that periportal fibrosis in mice did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. This observation suggests an interplay between zonated morphological disorders and metabolic zonation, a potentially clinically relevant finding. Therefore, we raised the hypothesis that periportal steatosis in mice may affect zonated drug metabolism parameters. Cross-species variation has not yet been systematically explored with respect to hepatic lobular geometry and CYP expression as needed for clinical translation. We hypothesized that lobular geometry as an anatomical feature is species-independent, whereas CYP zonal expression as a functional parameter is species-dependent. Method: We performed a detailed drug metabolism study in mice with periportal steatosis induced by feeding a high-fat methionine-choline reduced diet applied over two, respectively, four weeks. Drug metabolism was assessed in terms of the spatial distribution of drug-metabolizing CYP enzymes, CYP activity, and a pharmacokinetic study. For the cross-species analysis, we involved four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry to quantify lobular geometry and zonated expression of key cytochrome P450 (CYP) enzymes. Results: Periportal steatosis did not alter the pericentral expression pattern of the CYP enzymes. However, the activity of selected CYPs was related to the type and severity of steatosis. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. Using the newly developed automated image analysis pipeline, we observed that hepatic lobular geometry is rather robust, whereas zonated expression shows species-specific features, with mice being most similar to humans. Conclusion: In this thesis, we demonstrated that periportal pathology such as steatosis could affect certain features of hepatic drug metabolism, a metabolic process taking place in the pericentral region. We demonstrated the robustness of lobular geometry in four different species and described the impact of the given species on the spatial distribution of CYP proteins in normal livers. Perspective: Our planned future studies include assessing species-specific features of steatosis, including heterogeneity, and their implications for the spatial distribution of CYP expression. Based on this data, we want to perform a translational study using human samples to confirm the impact of periportal and pericentral steatosis on distinct parameters of drug metabolism.