Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity
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 lea...
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Published in | Archives of toxicology Vol. 96; no. 11; pp. 2967 - 2981 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Berlin/Heidelberg
Springer Berlin Heidelberg
01.11.2022
Springer Nature B.V |
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Abstract | 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. |
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AbstractList | 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. 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. Abstract 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. |
Author | Albrecht, Wiebke Cramer, Benedikt Friebel, Adrian Humpf, Hans-Ulrich Hoehme, Stefan Seddek, Abdel-latif Marchan, Rosemarie Ghallab, Ahmed Myllys, Maiju Hartl, Lukas Reiberger, Thomas Hengstler, Jan G. Trauner, Michael Degen, Gisela H. Hobloss, Zaynab Simbrunner, Benedikt Hassan, Reham Cadenas, Cristina Brackhagen, Lisa Mohammed, Elsayed S. I. González, Daniela |
Author_xml | – sequence: 1 givenname: Reham surname: Hassan fullname: Hassan, Reham organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University – sequence: 2 givenname: Adrian surname: Friebel fullname: Friebel, Adrian organization: Institute of Computer Science and Saxonian Incubator for Clinical Research (SIKT), University of Leipzig – sequence: 3 givenname: Lisa surname: Brackhagen fullname: Brackhagen, Lisa organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 4 givenname: Zaynab surname: Hobloss fullname: Hobloss, Zaynab organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 5 givenname: Maiju surname: Myllys fullname: Myllys, Maiju organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 6 givenname: Daniela surname: González fullname: González, Daniela organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 7 givenname: Wiebke surname: Albrecht fullname: Albrecht, Wiebke organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 8 givenname: Elsayed S. I. surname: Mohammed fullname: Mohammed, Elsayed S. I. organization: Department of Histology and Cytology, Faculty of Veterinary Medicine, South Valley University – sequence: 9 givenname: Abdel-latif surname: Seddek fullname: Seddek, Abdel-latif organization: Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University – sequence: 10 givenname: Rosemarie surname: Marchan fullname: Marchan, Rosemarie organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 11 givenname: Cristina surname: Cadenas fullname: Cadenas, Cristina organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 12 givenname: Benedikt surname: Cramer fullname: Cramer, Benedikt organization: Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster – sequence: 13 givenname: Hans-Ulrich surname: Humpf fullname: Humpf, Hans-Ulrich organization: Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster – sequence: 14 givenname: Lukas surname: Hartl fullname: Hartl, Lukas organization: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna – sequence: 15 givenname: Benedikt surname: Simbrunner fullname: Simbrunner, Benedikt organization: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna – sequence: 16 givenname: Thomas surname: Reiberger fullname: Reiberger, Thomas organization: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna – sequence: 17 givenname: Michael surname: Trauner fullname: Trauner, Michael organization: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna – sequence: 18 givenname: Stefan surname: Hoehme fullname: Hoehme, Stefan organization: Institute of Computer Science and Saxonian Incubator for Clinical Research (SIKT), University of Leipzig – sequence: 19 givenname: Gisela H. surname: Degen fullname: Degen, Gisela H. email: degen@ifado.de organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 20 givenname: Jan G. surname: Hengstler fullname: Hengstler, Jan G. email: hengstler@ifado.de organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund – sequence: 21 givenname: Ahmed orcidid: 0000-0003-0695-3403 surname: Ghallab fullname: Ghallab, Ahmed email: ghallab@ifado.de organization: Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University |
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CitedBy_id | crossref_primary_10_1016_j_ecoenv_2024_116277 crossref_primary_10_3390_antiox11122311 crossref_primary_10_1007_s00204_022_03395_y crossref_primary_10_1007_s00204_023_03565_6 crossref_primary_10_1080_03602532_2023_2195133 crossref_primary_10_1021_acsomega_4c01738 crossref_primary_10_1007_s00204_024_03688_4 crossref_primary_10_1007_s12550_024_00538_1 crossref_primary_10_1016_j_tox_2023_153630 crossref_primary_10_3390_cells12182331 crossref_primary_10_3390_toxins16020068 |
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Keywords | Albumin binding Toxicokinetics Intravital imaging Pharmacokinetics Mycotoxins |
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Snippet | Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and... Abstract Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the... |
SourceID | pubmedcentral proquest crossref springer |
SourceType | Open Access Repository Aggregation Database Publisher |
StartPage | 2967 |
SubjectTerms | 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 |
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Title | Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity |
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