Induction of the nuclear factor HIF-1alpha in acetaminophen toxicity: evidence for oxidative stress.
Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1alpha levels are a critical determinant of HIF activity. The induction of HIF-1alpha was examined in the livers of mice treated with a toxic dose of APAP (300 mg/kg i.p.) and sacrificed at 1, 2, 4, 8, and 12 h. HIF-1alpha was induced at 1-12 h and induction occurred prior to the onset of toxicity. Pre-treatment of mice with N-acetylcysteine (1200 mg/kg i.p.) prevented toxicity and HIF-1alpha induction. In further studies, hepatocyte suspensions were incubated with APAP (1 mM) in the presence of an oxygen atmosphere. HIF-1alpha was induced at 1 h, prior to the onset of toxicity. Inclusion of cyclosporine A (10 microM), an inhibitor of mitochondrial permeability transition, oxidative stress, and toxicity, prevented the induction of HIF-1alpha. Thus, HIF-1alpha is induced before APAP toxicity and can occur under non-hypoxic conditions. The data suggest a role for oxidative stress in the induction of HIF-1alpha in APAP toxicity.
James
Laura P
LP
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. jameslaurap@uams.edu
Donahower
Brian
B
Burke
Angela S
AS
McCullough
Sandra
S
Hinson
Jack A
JA
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000332:Aerobiosis; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology
D051793:Hypoxia-Inducible Factor 1; D000082:Acetaminophen; D010100:Oxygen; D000111:Acetylcysteine