dc.contributor.author
Albadry, Mohamed Awad Mohamed
dc.contributor.author
Küttner, Jonas
dc.contributor.author
Grzegorzewski, Jan
dc.contributor.author
Dirsch, Olaf
dc.contributor.author
Kindler, Eva
dc.contributor.author
Klopfleisch, Robert
dc.contributor.author
Liska, Vaclav
dc.contributor.author
Moulisova, Vladimira
dc.contributor.author
Nickel, Sandra
dc.contributor.author
Palek, Richard
dc.contributor.author
Rosendorf, Jachym
dc.contributor.author
Saalfeld, Sylvia
dc.contributor.author
Settmacher, Utz
dc.contributor.author
Tautenhahn, Hans-Michael
dc.contributor.author
König, Matthias
dc.contributor.author
Dahmen, Uta
dc.date.accessioned
2024-06-05T07:31:46Z
dc.date.available
2024-06-05T07:31:46Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/43756
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-43471
dc.description.abstract
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.
en
dc.format.extent
20 Seiten
dc.rights
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
liver lobular geometry
en
dc.subject
metabolic zonation
en
dc.subject
drug metabolism
en
dc.subject
cytochrome P450
en
dc.subject
glutamine synthetase
en
dc.subject
interspecies
en
dc.subject
image analysis
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
dc.title
Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4
dc.type
Wissenschaftlicher Artikel
dc.date.updated
2024-06-03T07:03:19Z
dcterms.bibliographicCitation.articlenumber
1404938
dcterms.bibliographicCitation.doi
10.3389/fphar.2024.1404938
dcterms.bibliographicCitation.journaltitle
Frontiers in Pharmacology
dcterms.bibliographicCitation.volume
15
dcterms.bibliographicCitation.url
https://doi.org/10.3389/fphar.2024.1404938
refubium.affiliation
Veterinärmedizin
refubium.affiliation.other
Institut für Tierpathologie
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1663-9812
refubium.resourceType.provider
DeepGreen