As the Society of Toxicology Annual Meeting and ToxExpo are wrapping up, we would like to highlight a few relevant publications in safety toxicity applications.
A novel human alanine aminotransferase 1 (hALT1) specific enzyme-linked immunosorbent assay (ELISA) developed by PhoenixBio is described in a publication “Detection of acute toxicity of aflatoxin B1 to human hepatocytes in vitro and in vivo using chimeric mice with humanized livers”. Sandwich ELISA was established using two different monoclonal antibodies (mAbs) specific for hALT1, and the developed assay shows no cross reactivity with either hALT2 or mouse-derived ALT. Such a method allows for monitoring human hepatocyte injury throughout the in-life phases of chimeric mice with a humanized liver (PXB-mice) and can support liver histology data. The method is a valuable tool in drug induced liver injury studies, as well as in other toxicity-related evaluations.
In 2020, the journal “Toxicological Sciences” selected Sumitomo Chemical Company’s paper as a FEATURED publication. We are incredibly proud that our model, the PXB-mouse®, helped generate such high-quality scientific results. The paper compares hepatic effects of phenobarbital in various preclinical rodent models including chimeric mice transplanted with rat hepatocytes and with human hepatocytes (PXB-mouse®). The study demonstrated that the PXB-mouse® responds to rodent CAR activators in a human-like manner. In two sets of experiments, authors share data obtained with Sprague-Dawley (SD) rats, CAR KO rats, chimeric mice with rat hepatocytes, hCAR/hPXR mice, wild-type (CD-1) mice, and the PXB-mouse®. Hierarchical clustering analysis shows benefits of using the PXB-mouse® over other rodent models studied. For more details: https://lnkd.in/eyYmkzj
Another publication in “Toxicological Sciences” studied the hepatic toxicity caused by KMTR2, an anti-human TRAIL-R2 monoclonal antibody, in the PXB-mouse®. In the study, conducted by Kyowa Hakko Kirin, the analyses of blood chemistry, liver histopathology, hepatic gene expression, and toxicokinetic parameters were performed. The results show that apoptosis was induced only in human hepatocytes but not in mouse hepatocytes. The concentration of serum cCK18 (marker of human-specific apoptosis) was elevated from 48 hours after KMTR2 administration through 168 hours. A strong correlation between cCK18 and human ALT1 concentrations was observed.
Contact Us if you are interested in the further details of the discussed publications or would like to discuss other questions related to the preclinical toxicity evaluation in chimeric mice with a humanized liver.
The summary was prepared by Dr. S. Sapelnikova.