Back to Search
Start Over
Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.
- Source :
-
Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2012 Apr; Vol. 110 (4), pp. 327-34. Date of Electronic Publication: 2011 Nov 09. - Publication Year :
- 2012
-
Abstract
- Up-regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. This study was conducted to examine the relationship of hypoxia-inducible factor 1α (HIF-1α) to VEGF and hepatocyte regeneration in APAP toxicity using an inhibitor of HIF-1α DNA-binding activity, echinomycin (EC). B6C3F1 male mice were treated with APAP (200 mg/kg IP), followed by EC (0.15 mg IP) and killed at 4 hr. Serum alanine aminotransferase (ALT), necrosis, hepatic glutathione (GSH) and APAP protein adducts were comparable in the APAP/EC and the APAP/veh mice at 4 hr. Additional studies showed that high dose EC (0.3 mg) reduced hepatic VEGF but also lowered hepatic GSH. Subsequent studies were performed using the 0.15-mg dose of EC. Although EC 0.15 mg had no effect on hepatic VEGF levels at 8 hr, by 24 hr VEGF levels were decreased by 40%. Toxicity (ALT and histopathology) was comparable in the APAP and APAP/EC groups at 24 and 48 hr. Proliferating cell nuclear antigen expression was reduced by both Western blot analysis and immunohistochemical staining in the APAP/EC mice at 48 hr. The data support the hypothesis that induction of HIF-1α, its binding to DNA and subsequent expression of VEGF are important factors in hepatocyte regeneration in APAP toxicity in the mouse.<br /> (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)
- Subjects :
- Animals
Chemical and Drug Induced Liver Injury etiology
DNA metabolism
Dose-Response Relationship, Drug
Echinomycin administration & dosage
Gene Expression Regulation drug effects
Hepatocytes metabolism
Hypoxia-Inducible Factor 1, alpha Subunit drug effects
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Liver Regeneration drug effects
Male
Mice
Proliferating Cell Nuclear Antigen genetics
Time Factors
Vascular Endothelial Growth Factor A drug effects
Vascular Endothelial Growth Factor A genetics
Acetaminophen toxicity
Chemical and Drug Induced Liver Injury drug therapy
Echinomycin pharmacology
Hepatocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1742-7843
- Volume :
- 110
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Basic & clinical pharmacology & toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 21985601
- Full Text :
- https://doi.org/10.1111/j.1742-7843.2011.00812.x