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 survival in rats treated with thioacetamide (TAA) was investigated.


METHODS
In one experiment, the effect of DFMO on survival of rats with TAA-induced acute hepatocellular necrosis was determined. In another experiment, blood and liver specimens were obtained from DFMO or saline-treated rats 24 h after the administration of TAA for determinations of serum alanine aminotransferase (ALT) and liver content of polyamines and microsomal cytochrome P-450 and for assessment of hepatic histology.


METHODS
Liver polyamines were determined by reversed-phase HPLC and microsomal cytochrome P-450 content by dithionite-difference spectroscopy of CO-treated homogenates. The severity of hepatocellular necrosis was scored blindly.


RESULTS
TAA-treated rats that received DFMO survived longer than saline-treated controls (P < 0.01). Serum ALT and liver putrescine concentrations were lower and the histological severity of acute hepatocellular necrosis was less in DFMO-treated rats with TAA-induced hepatocellular necrosis than in saline-treated controls (P < 0.05, P < 0.01 and P < 0.05, respectively). Total cytochrome P-450 levels were similar in DFMO and saline-treated rats with TAA-induced hepatocellular necrosis.


CONCLUSIONS
DFMO increases survival in TAA-induced fulminant hepatic failure by decreasing the severity of acute hepatocellular necrosis. The beneficial effects of DFMO do not appear to be mediated 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.
Yurdaydin
C
C
Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, MD, USA. yurdaydi@dialp.ankara.edu.tr
Swain
M G
MG
Mininberg
E D
ED
Vergalla
J
J
Kleiner
D
D
Paul
S M
SM
Jones
E A
EA
D000818:Animals; D003577:Cytochrome P-450 Enzyme System; D004195:Disease Models, Animal; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide
D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D013853:Thioacetamide; D003577:Cytochrome P-450 Enzyme System; D009955:Ornithine Decarboxylase; D000518:Eflornithine