Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity

• Published in: Archives of toxicology Vol. 96; no. 11; pp. 2967 - 2981
• Main Authors: Hassan, Reham, Friebel, Adrian, Brackhagen, Lisa, Hobloss, Zaynab, Myllys, Maiju, González, Daniela, Albrecht, Wiebke, Mohammed, Elsayed S. I., Seddek, Abdel-latif, Marchan, Rosemarie, Cadenas, Cristina, Cramer, Benedikt, Humpf, Hans-Ulrich, Hartl, Lukas, Simbrunner, Benedikt, Reiberger, Thomas, Trauner, Michael, Hoehme, Stefan, Degen, Gisela H., Hengstler, Jan G., Ghallab, Ahmed
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2022; Springer Nature B.V
• Subjects: Albumin; Archives & records; Bile ducts; Binding; Biomedical and Life Sciences; Biomedicine; Blood vessels; Breast cancer; Capillaries; Environmental Health; Epithelial cells; Epithelium; Filtration; Fluorescence; Gastroenterology; Hepatocytes; Hepatology; Hepatotoxicity; Inflammatory diseases; Internal medicine; Kidneys; Liver; Liver diseases; Mycotoxins; Occupational Medicine/Industrial Medicine; Ochratoxin A; Pharmacokinetics; Pharmacology/Toxicology; Plasma; Proteins; Serum albumin; Substrates; Tissues; Toxicity; Toxicokinetics and Metabolism; Toxicology; Veterinary medicine; Albumin binding; Toxicokinetics; Intravital imaging; Pharmacokinetics; Mycotoxins
• DOI: 10.1007/s00204-022-03361-8
• ISSN: 0340-5761

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The ‘ lack-of-delivery-concept ’ postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the ‘ concept-of-higher-free-fraction ’ argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the ‘ concept-of-higher-free-fraction ’ in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.