Ketamine-induced hepatoprotection: the role of heme oxygenase-1

Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1360-9. doi: 10.1152/ajpgi.00038.2009. Epub 2009 Apr 16.


Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Carbon Monoxide / pharmacology
  • Chemical and Drug Induced Liver Injury
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / physiology*
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Lipopolysaccharides / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Liver Diseases / blood
  • Liver Diseases / metabolism
  • Liver Diseases / prevention & control*
  • Male
  • Metalloporphyrins / pharmacology
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • PPAR gamma / metabolism
  • Protoporphyrins / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Metalloporphyrins
  • NF-kappa B
  • PPAR gamma
  • Protoporphyrins
  • Ketamine
  • Carbon Monoxide
  • tin protoporphyrin IX
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Alanine Transaminase