Abstract
Large interspecies differences between rats and mice concerning the hepatotoxicity and carcinogenicity of aflatoxin B1 (AFB1) are known, with mice being more resistant. However, a comprehensive interspecies comparison including subcellular liver tissue compartments has not yet been performed. In this study, we performed spatio-temporal intravital analysis of AFB1 kinetics in the livers of anesthetized mice and rats. This was supported by time-dependent analysis of the parent compound as well as metabolites and adducts in blood, urine, and bile of both species by HPLC–MS/MS. The integrated data from intravital imaging and HPLC–MS/MS analysis revealed major interspecies differences between rats and mice: (1) AFB1-associated fluorescence persisted much longer in the nuclei of rat than mouse hepatocytes; (2) in the sinusoidal blood, AFB1-associated fluorescence was rapidly cleared in mice, while a time-dependent increase was observed in rats in the first three hours after injection followed by a plateau that lasted until the end of the observation period of six hours; (3) this coincided with a far stronger increase of AFB1-lysine adducts in the blood of rats compared to mice; (4) the AFB1-guanine adduct was detected at much higher concentrations in bile and urine of rats than mice. In both species, the AFB1-glutathione conjugate was efficiently excreted via bile, where it reached concentrations at least three orders of magnitude higher compared to blood. In conclusion, major differences between mice and rats were observed, concerning the nuclear persistence, formation of AFB1-lysine adducts, and the AFB1-guanine adducts.
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AG, JGH, GHD helped in study concept and design, data analysis and interpretation, drafting the manuscript; AG, RH were involved in intravital imaging, data acquisition; RH, ZH, MM, DG contributed to animal experiments, data acquisition and writing of the manuscript; WA performed toxicokinetic analysis of the data and contributed to writing of the manuscript; AF, SH contributed to image analysis and writing of the manuscript; H-UH involved in study concept and design, supervision of the HPLC–MS/MS analysis, data analysis and interpretation and contributed to writing of the manuscript; ME contributed to data analysis and interpretation and writing of the manuscript; JV helped in preparation of reference compounds and HPLC–MS/MS analysis; AG, BC contributed to HPLC–MS/MS analysis and data interpretation, data acquisition and writing of the manuscript.
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Hassan, R., Gerdemann, A., Cramer, B. et al. Integrated data from intravital imaging and HPLC–MS/MS analysis reveal large interspecies differences in AFB1 metabolism in mice and rats. Arch Toxicol 98, 1081–1093 (2024). https://doi.org/10.1007/s00204-024-03688-4
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DOI: https://doi.org/10.1007/s00204-024-03688-4