Species-specific liver microtissues reveal divergent adverse responses to fialuridine treatment.
8 affiliations
- 1InSphero AG, Schlieren, Switzerland.
- 2PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
- 3Merck Healthcare KGaA, Darmstadt, Germany.
- 4Genentech, South San Francisco, CA, USA.
- 5Global Investigative Toxicology, Preclinical Safety, Sanofi, Cambridge, MA, 02141, USA.
- 6Global Discovery and Investigative Toxicology, Pfizer, Groton, CT, 06340, USA.
- 7MicroMatrices Associate Ltd, Dundee, Scotland.
- 8InSphero AG, Schlieren, Switzerland. [email protected].
Abstract
The safety of drug candidates is routinely evaluated using animal models; however, physiological differences between species can lead to different responses. In vitro safety testing with cells derived from preclinical species can help support mechanistic investigations and assess the relevance, or lack thereof, of in vivo preclinical toxicity findings to human. To that end, liver microtissues (LiMTs) from human (Homo sapiens), rat (Rattus norvegicus), dog (Canis familiaris), and monkey (Macaca fascicularis) were used to investigate the species-specific responses to fialuridine, a nucleoside analogue, that resulted in fatal hepatotoxicity in human clinical trials. The morphology and functionality of these models was assessed over seven days in culture by monitoring ATP levels, albumin production, and cytochrome P450 (CYP450) activity. Fialuridine is markedly more cytotoxic to human LiMTs than to their animal counterparts. Moreover, whole genome transcriptomic analysis showed that fialuridine elicits distinct gene expression responses in human versus animal LiMTs, including the upregulation DNA damage repair pathways and induction of apoptosis. Overall, these findings are consistent with historical clinical and preclinical observations, showing these species-specific LiMTs provide a physiological, scalable, and reproducible in vitro platform for investigating interspecies differences in drug metabolism and hepatotoxicity. Integrating these models into preclinical safety assessment prior to first-in-human studies offers a robust, weight-of-evidence approach to understand species-specific responses and refine human risk assessment.
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BibTeX
@article{colombo2026speciesspecific,
title = {{Species-specific liver microtissues reveal divergent adverse responses to fialuridine treatment.}},
author = {Maria Vittoria Colombo and Agnieszka Pawlowska and Friederike Wenz and Donna Busler and Nicolas Sierro and Yang Xiang and Emmanuel Guedj and Philip Hewitt and Leah M Norona and Piyush Bajaj and Jonathan P Jackson and Simon Plummer and Bruno G H Filippi},
journal = {Cell biology and toxicology},
year = {2026},
month = aug,
doi = {10.1007/s10565-026-10246-4},
url = {https://europepmc.org/article/MED/42972155},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Species-specific liver microtissues reveal divergent adverse responses to fialuridine treatment.
AU - Maria Vittoria Colombo
AU - Agnieszka Pawlowska
AU - Friederike Wenz
AU - Donna Busler
AU - Nicolas Sierro
AU - Yang Xiang
AU - Emmanuel Guedj
AU - Philip Hewitt
AU - Leah M Norona
AU - Piyush Bajaj
AU - Jonathan P Jackson
AU - Simon Plummer
AU - Bruno G H Filippi
PY - 2026
DA - 2026/08/05
JO - Cell biology and toxicology
DO - 10.1007/s10565-026-10246-4
UR - https://europepmc.org/article/MED/42972155
AB - The safety of drug candidates is routinely evaluated using animal models; however, physiological differences between species can lead to different responses. In vitro safety testing with cells derived from preclinical species can help support mechanistic investigations and assess the relevance, or lack thereof, of in vivo preclinical toxicity findings to human. To that end, liver microtissues (LiMTs) from human (Homo sapiens), rat (Rattus norvegicus), dog (Canis familiaris), and monkey (Macaca fascicularis) were used to investigate the species-specific responses to fialuridine, a nucleoside analogue, that resulted in fatal hepatotoxicity in human clinical trials. The morphology and functionality of these models was assessed over seven days in culture by monitoring ATP levels, albumin production, and cytochrome P450 (CYP450) activity. Fialuridine is markedly more cytotoxic to human LiMTs than to their animal counterparts. Moreover, whole genome transcriptomic analysis showed that fialuridine elicits distinct gene expression responses in human versus animal LiMTs, including the upregulation DNA damage repair pathways and induction of apoptosis. Overall, these findings are consistent with historical clinical and preclinical observations, showing these species-specific LiMTs provide a physiological, scalable, and reproducible in vitro platform for investigating interspecies differences in drug metabolism and hepatotoxicity. Integrating these models into preclinical safety assessment prior to first-in-human studies offers a robust, weight-of-evidence approach to understand species-specific responses and refine human risk assessment.
SN - 0742-2091
SN - 1573-6822
ER -