Abstract Inorganic arsenic is a known human carcinogen associated with liver and bladder cancer. Among its species, sodium arsenite (iAsIII) undergoes complex hepatic biotransformation, producing methylated metabolites such as monomethylated (MMA) and dimethylated (DMA) forms. However, its human-relevant mechanisms of metabolism and carcinogenicity remain unclear due to species differences in arsenic biotransformation. To clarify these differences, we employed a humanized-liver (HL) mouse model, in which mouse hepatocytes are replaced with human hepatocytes, to investigate the metabolism and carcinogenic potential of iAsIII. HL and wild type (WT) mice were administrated 50 ppm of iAsIII in drinking water for 4 weeks. Urine, liver, and bladder samples were collected for analysis. Urinary arsenic speciation was determined using high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Histopathology and immunohistochemistry were performed on both liver and bladder tissue, and gene expression profiles were analyzed using RNA sequencing and microarray, respectively. Urinary arsenic speciation revealed distinct species-dependent differences. Dimethylarsinic acid (DMAV) was the predominant urinary arsenic metabolite in both HL and WT mice. Total urinary arsenic in HL mice was lower than in WT mice, but the distribution of metabolites differed markedly. The proportion of MMAV in HL mice (26.4%) was substantially higher than in WT mice (4.7%), whereas DMAV accounted for 58.5% in HL and 80.7% in WT mice. This urinary metabolite pattern more closely resembled that observed in humans exposed to inorganic arsenic. Hepatic arsenic methyltransferase (As3MT) expression was significantly elevated in WT mice treated with iAsIII but tended to decrease in HL mice. Gene expression profiles of liver and bladder tissues of HL mice also differed from those of WT mice. Immunohistochemical analysis of proliferation markers is currently underway to evaluate whether iAsIII promotes hepatocellular and urothelial proliferative response. Arsenic content in the liver is also currently under investigation, and pathway analysis of the transcriptomic data using Ingenuity Pathway Analysis (IPA) is ongoing to identify key molecular alterations for further validation. In conclusion, these findings indicate that human hepatocytes exhibit lower methylation capacity, resulting in higher proportions of toxic MMA species, suggesting that humans may be more susceptible to arsenic than mice. Furthermore, the HL mouse model effectively reflects human arsenic metabolism and provides a valuable in vivo platform for elucidating human-relevant metabolic, toxicological, and molecular mechanisms underlying arsenic-induced hepatotoxicity and carcinogenicity. Citation Format: Arpamas Vachiraarunwong, Shugo Suzuki, Masaki Fujioka, Runjie Guo, Guiyu Qiu, Yurina Kawamura, Ikue Noura, Anna Kakehashi, Hideki Wanibuchi, Min Gi. Metabolism and carcinogenic potential of inorganic arsenic in humanized-liver mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3373.
Vachiraarunwong et al. (Fri,) studied this question.