Ketamine-induced hepatoprotection: the role of heme oxygenase-1.
Am J Physiol Gastrointest Liver Physiol. 2009 June; 296(6): G1360–
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.
Alanine Transaminase, Animals, Anti-Inflammatory Agents, Non-Steroidal, Carbon Monoxide, Cyclooxygenase 2, Drug-Induced Liver Injury, Enzyme Inhibitors, Gene Expression, Heme Oxygenase (Decyclizing), Ketamine, Lipopolysaccharides, Liver, Liver Diseases, Male, Metalloporphyrins, NF-kappa B, Nitric Oxide Synthase Type II, PPAR gamma, Protoporphyrins, Rats, Rats, Sprague-Dawley, Up-Regulation