| Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues. | |
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MedLine Citation:
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PMID: 20144635 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A novel in vitro model to investigate time-dependent and concentration-dependent responses in blood cells and hemolytic events is studied for rat, dog, and human tissues. Whole blood is co-cultured with a precision-cut liver slice. Methimazole (MMI) was selected as a reference compound, since metabolism of its imidazole thione moiety is linked with hematologic disorders and hepatotoxicity. An oxidative stress response occurred in all three species, marked by a decline in blood GSH levels by 24 h that progressed, and preceded hemolysis, which occurred at high MMI concentrations in the presence of a liver slice with rat (>or=1000 microM at 48 h) and human tissues (>or=1000 microM at 48 h, >or=750 microM at 72 h) but not dog. Human blood-only cultures exhibited a decline of GSH levels but minimal to no hemolysis. The up-regulation of liver genes for heme degradation (Hmox1 and Prdx1), iron cellular transport (Slc40a1), and GSH synthesis and utilization (mGST1 and Gclc) were early markers of the oxidative stress response. The up-regulation of the Kupffer cell lectin Lgals3 gene expression indicated a response to damaged red blood cells, and Hp (haptoglobin) up-regulation is indicative of increased hemoglobin uptake. Up-regulation of liver IL-6 and IL-8 gene expression suggested an activation of an inflammatory response by liver endothelial cells. In summary, MMI exposure led to an oxidative stress response in blood cells, and an up-regulation of liver genes involved with oxidative stress and heme homeostasis, which was clearly separate and preceded frank hemolysis. |
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Authors:
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Alison E M Vickers; John R Sinclair; Robyn L Fisher; Stephen R Morris; William Way |
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Publication Detail:
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Type: Journal Article Date: 2010-02-06 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 244 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-05 Completed Date: 2010-04-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 354-65 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Drug Safety Evaluation, Allergan, 2525 Dupont Dr, Irvine, CA 92612, USA. vickers_alison@allergan.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Markers / metabolism Cation Transport Proteins / metabolism Coculture Techniques Dogs Erythrocytes / drug effects, metabolism* Female Gene Expression / drug effects Heme Oxygenase-1 / metabolism Hemolysis / drug effects* Humans Liver / drug effects, metabolism* Male Methimazole / chemistry, toxicity Models, Biological Oxidative Stress / drug effects* Peroxiredoxins / metabolism Rats Rats, Sprague-Dawley Tissue Donors Up-Regulation / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Biological Markers; 0/Cation Transport Proteins; 0/metal transporting protein 1; 60-56-0/Methimazole; EC 1.11.1.15/PRDX1 protein, human; EC 1.11.1.15/Peroxiredoxins; EC 1.14.99.3/HMOX1 protein, human; EC 1.14.99.3/Heme Oxygenase-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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