Hyperbaric oxygen reduces acetaminophen toxicity and increases HIF-1alpha expression

Acad Emerg Med. 2006 Jul;13(7):707-14. doi: 10.1197/j.aem.2006.01.029. Epub 2006 Apr 24.

Abstract

Objectives: To investigate the effect of hyperbaric oxygen (HBO2) on acetaminophen (APAP)-induced hepatotoxicity. The authors further evaluated the effects of APAP poisoning and HBO2 on the expression and function of hypoxia-inducible factor 1-alpha (HIF-1alpha) in an effort to further describe the mechanisms of APAP-induced hepatotoxicity. In vitro assays were performed to better understand the effects of HBO2 on HIF-1alpha function.

Methods: In vivo, four groups of C57BL/6 mice were treated as follows: APAP only, APAP followed by HBO2, HBO2 only, and untreated shams. Plasma alanine aminotransferase activity was measured, and hepatic HIF-1alpha induction was determined by Western blot. In vitro, cultured HEP G2 hepatocytes were exposed to HBO2, hypoxia (2.5% O2), or normoxia. HIF-1alpha DNA-binding and transcriptional activity were assessed.

Results: Alanine aminotransferase activity was reduced in the APAP+HBO2 group (2,606 IU/L +/- 4,080; vs. APAP: 6,743 +/- 3,397, p = 0.01 at 6 hours). APAP-only, HBO2-only, and APAP+HBO2 treatments all increased HIF-1alpha expression relative to shams (p = 0.02, p = 0.02, and p < 0.01, respectively). HBO2 increased HIF-1alpha DNA binding 5.7 (+/- 1.2)-fold relative to controls (p < 0.01); however, a parallel increase in HIF functional transcriptional activity did not occur.

Conclusions: Hyperbaric oxygen reduced early APAP-induced hepatocellular injury. APAP poisoning increases HIF-1alpha protein levels and functional activity. HBO2 increases HIF-1alpha protein levels and DNA binding without a corresponding increase in transcriptional activity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / toxicity*
  • Alanine Transaminase / blood
  • Animals
  • Biomarkers / metabolism
  • Disease Models, Animal
  • Drug-Related Side Effects and Adverse Reactions / metabolism
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Drug-Related Side Effects and Adverse Reactions / therapy
  • Glucose Transporter Type 1 / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hyperbaric Oxygenation / methods*
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism

Substances

  • Biomarkers
  • Glucose Transporter Type 1
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Slc2a1 protein, mouse
  • Transcription Factors
  • Acetaminophen
  • Alanine Transaminase