Submitted on January 30, 2009
Revised on April 3, 2009
Accepted on April 9, 2009
Ketamine Induced Hepatoprotection: the Role of Heme Oxygenase-1
James W. Suliburk1, Jeremy L. Ward1, Kenneth S. Helmer1, Sasha D Adams2, Brian S. Zuckerbraun3, and David W. Mercer4*
1 University of Texas Medical School at Houston
2 University of Texas Medical School
3 University of Pittsburgh
4 UT-Houston Medical School/LBJ General Hospital
* To whom correspondence should be addressed. E-mail: david.w.mercer{at}uth.tmc.edu.
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 saline or ketamine (70 mg/kg IP) concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 µmol/kg IP) or saline. Another group of rats received inhalational CO (250 ppm over 1 hour) or room air. All rats were given saline or LPS (20 mg/kg IP) 1h later and sacrificed 5h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-
B and PPAR-
(EMSA) analysis, and iNOS and COX-2 mRNA (RT-PCR) analysis. Serum was collected to measure ALT 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. While CO abolished the ability of LPS to diminish PPAR- activity, it enhanced NF-B activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end-product CO.
