Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity

Abstract

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

Analysis of the Bile Acid Composition in a Fibroblast Growth Factor 19-Expressing Liver-Humanized Mouse Model and Its Use for CYP3A4-Mediated Drug–Drug Interaction Studies

“…Such liver-humanized mouse models have a variety of potential applications, for example in studies of human-liver infectious diseases (Dandri et al, 2001;Mercer et al, 2001;Kosaka et al, 2013;Sayed et al, 2017;Tyagi et al, 2018), the testing of gene therapy vectors (Kakuni et al, 2013;Lisowski et al, 2014) or of other therapeutic agents. With regard to the latter, there are numerous studies in which these models were used, for example, in drug metabolism (Sanoh et al, 2015;Nakada et al, 2016;Dickie et al, 2017;Wilson et al, 2018;Uehara et al, 2022b), hepatotoxicity (Xu et al, 2014;Xu et al, 2015b;Xu et al, 2015a;Nihira et al, 2019;Eguchi et al, 2021) or DDI studies (Hasegawa et al, 2012;Yamazaki et al, 2013;Uchida et al, 2018;Uehara et al, 2022a).…”