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Effect of Exogenous VEGF on Acetaminophen Toxicity
Author(s) -
Donahower Brian C,
McCullough Sandra,
Simpson Pippa,
Lamps Laura,
Hinson Jack,
James Laura
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a812-b
Subject(s) - vegf receptors , toxicity , vascular endothelial growth factor , acetaminophen , pharmacology , chemistry , medicine , glutathione , endocrinology , biochemistry , enzyme
Vascular endothelial growth factor (VEGF) is best known as a mitogen for endothelial cells. We previously showed that VEGF was markedly increased in the late stages of acetaminophen (APAP) toxicity and that treatment with a VEGF receptor inhibitor delayed recovery in mice. In this pilot study, we examined the effect of exogenous VEGF on the early stages of APAP toxicity. C57Bl/6 mice received human recombinant (hr)VEGF (50 ug sq) 30 min prior to APAP (200 mg/kg IP) and were sacrificed at 2, 4, and 8 hr. Another group of mice received PBS vehicle 30 minutes prior to APAP and were sacrificed at the same time points. Hepatic hrVEGF levels peaked at 2 hr and remained elevated at 4 and 8 hr (p < 0.05). ALT values were comparable between the two groups at 2 and 4 hr. ALT values were lower in the mice that received hrVEGF (7803 ± 546 vs. 4310 ± 777 IU/L, p < 0.05) at 8 hr. Glutathione and APAP protein adduct levels were comparable between the VEGF treated mice and the vehicle treated mice at all time points. Hepatic IL6 levels were also measured as IL6 has previously been shown to be important in recovery following APAP toxicity. IL6 levels were comparable between the two groups at 2 and 4 hr, but were lower in the VEGF treated mice compared to the APAP/vehicle group at 8 hr (184 ± 29 vs. 377 ± 49 pg/g, p < 0.05). The data suggest that exogenous VEGF alters the later stages of APAP toxicity and that a negative feedback mechanism involving IL6 may be involved.