Effect of Exogenous VEGF on Acetaminophen Toxicity

Up-regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. The following study was conducted to examine the relationship of hypoxia inducible factor 1α (HIF-1α) to VEGF and hepatocyte regeneration in APAP toxicity by 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 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) were 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 vascular endothelial growth factor are important factors in hepatocyte regeneration in APAP toxicity in the mouse.

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Echinomycin Decreases Induction of Vascular Endothelial Growth Factor and Hepatocyte Regeneration in Acetaminophen Toxicity in Mice

Milesi-Hallé

McCullough

Hinson

et al. 2011

Basic Clin Pharma Tox

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Effect of Exogenous VEGF on Acetaminophen Toxicity

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Echinomycin Decreases Induction of Vascular Endothelial Growth Factor and Hepatocyte Regeneration in Acetaminophen Toxicity in Mice

Echinomycin Decreases Induction of Vascular Endothelial Growth Factor and Hepatocyte Regeneration in Acetaminophen Toxicity in Mice

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