EFFECT OF INHIBITION OF ORNITHINE DECARBOXYLASE ACTIVITY IN A MODEL OF ACUTE HEPATOCELLULAR NECROSIS

Objective The effect of blockade of the enzyme ornithine decarboxylase by difluoromethylornithine (DFMO) on hepatocellular necrosis and surv ival in rats treated with thioacetamide (TAA) was investigated. Design In one experiment, the effect of DFMO on survival of rats with TAA-in duced acute hepatocellular necrosis was determined. In another experim ent, blood and liver specimens were obtained from DFMO or saline-treat ed rats 24 h after the administration of TAA for determinations of ser um alanine aminotransferase (ALT) and liver content of polyamines and microsomal cytochrome P-450 and for assessment of hepatic histology, M ethods Liver polyamines were determined by reversed-phase HPLC and mic rosomal cytochrome P-450 content by dithionite-difference spectroscopy of CO-treated homogenates, The severity of hepatocellular necrosis wa s scored blindly. Results TAA-treated rats that received DFMO survived longer than saline-treated controls (P < 0.01). Serum ALT and liver p utrescine concentrations were lower and the histological severity of a cute hepatocellular necrosis was less in DFMO-treated rats with TAA-in duced hepatocellular necrosis than in saline-treated controls (P < 0.0 5, P < 0.01 and P < 0.05, respectively). Total cytochrome P-450 levels were similar in DFMO and saline-treated rats with TAA-induced hepatoc ellular necrosis. Conclusions DFMO increases survival in TAA-induced f ulminant hepatic failure by decreasing the severity of acute hepatocel lular necrosis. The beneficial effects of DFMO do not appear to be med iated by its effects on polyamine metabolism, but may be attributable to an effect of DFMO on thioacetamide metabolism or on an alternative pathway of ornithine metabolism, Eur J Gastroenterol Hepatol 10:503-50 7 (C) 1998 Lippincott-Raven Publishers.