Association of Methotrexate-Induced Renal Toxicity in Humanized-Liver Mice With Human AOX1-Derived 7-Hydroxymethotrexate.

Authors

Yuki Obata, Shotaro Uehara, Yuichiro Higuchi, Masahiko Yasuda, Takaya Homma, Yukari Totsuka, Hiroshi Suemizu

Published in

Journal of applied toxicology : JAT. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

High doses of methotrexate are widely used, but its clinical application is limited by renal toxicity. The poorly soluble metabolite 7-hydroxymethotrexate contributes to renal injury, potentially through intratubular precipitation; however, its formation differs across species, complicating the evaluation of human-relevant toxicity in conventional animal models. In this study, methotrexate-induced renal toxicity was investigated using chimeric mice with humanized livers (humanized-liver mice). The pharmacokinetics of methotrexate and its major metabolite, 7-hydroxymethotrexate, were characterized in humanized-liver mice and compared with those in nontransplanted mice. Following the administration of a single oral dose, plasma concentrations and area under the curves of methotrexate and 7-hydroxymethotrexate were higher in humanized-liver mice than in control mice, and the urinary metabolite-to-parent ratio in humanized-liver mice was comparable to that reported in humans. Repeated methotrexate administration significantly increased blood urea nitrogen and creatinine levels, indicating impaired renal function. Necrosis of tubular epithelial cells and eosinophilic debris within the tubules were observed in the kidneys of humanized-liver mice, along with the accumulation of methotrexate and 7-hydroxymethotrexate, but not in control mice. Hepatic cytosolic methotrexate 7-hydroxylation activity in humanized-liver mice showed kinetic properties and inhibitor sensitivity consistent with human aldehyde oxidase, supporting this enzyme's role in metabolite formation. Thus, humanized-liver mice recapitulate key features of methotrexate-induced renal toxicity associated with human-relevant metabolism, providing a useful in vivo platform to evaluate organ toxicity in the context of human pharmacokinetics.

PMID:
42806748
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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