Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4.

Autor:	Albadry M; Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena University Hospital, Jena, Germany.; Department of Pathology, Faculty of Veterinary Medicine, Menoufia University, Shebin Elkom, Menoufia, Egypt., Küttner J; Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena University Hospital, Jena, Germany.; Institute for Theoretical Biology, Institute für Biologie, Systems Medicine of the Liver, Humboldt-Universität zu Berlin, Berlin, Germany., Grzegorzewski J; Institute for Theoretical Biology, Institute für Biologie, Systems Medicine of the Liver, Humboldt-Universität zu Berlin, Berlin, Germany., Dirsch O; Institute for Pathology, BG Klinikum Unfallkrankenhaus Berlin, Berlin, Germany., Kindler E; Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany., Klopfleisch R; Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany., Liska V; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.; Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Moulisova V; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Nickel S; Clinic and Polyclinic for Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Leipzig, Germany., Palek R; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.; Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Rosendorf J; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.; Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Saalfeld S; Institute of Biomedical Engineering and Informatics, Ilmenau University of Technology, Ilmenau, Germany., Settmacher U; Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany., Tautenhahn HM; Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena University Hospital, Jena, Germany.; Clinic and Polyclinic for Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Leipzig, Germany., König M; Institute for Theoretical Biology, Institute für Biologie, Systems Medicine of the Liver, Humboldt-Universität zu Berlin, Berlin, Germany., Dahmen U; Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena University Hospital, Jena, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 May 16; Vol. 15, pp. 1404938. Date of Electronic Publication: 2024 May 16 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1404938
Abstrakt:	There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in 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. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Albadry, Küttner, Grzegorzewski, Dirsch, Kindler, Klopfleisch, Liska, Moulisova, Nickel, Palek, Rosendorf, Saalfeld, Settmacher, Tautenhahn, König and Dahmen.)
Databáze:	MEDLINE
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