Effect of a potent iNOS inhibitor (ONO-1714) on acetaminophen-induced hepatotoxicity in the rat.
Overproduction of nitric oxide (NO) in the liver has been implicated as an important event in endotoxin shock and in other models of hepatic inflammation and injury. The present study was undertaken to evaluate the effect of ONO-1714, a potent and specific inhibitor of inducible NO synthase (iNOS), on acetaminophen-induced hepatotoxicity in the rats. Oral administration of ONO-1714 dose-dependently inhibited NOx (NO2- and NO3-) accumulation in rat plasma after lipopolysaccharide (LPS) treatment. Intraperitoneal acetaminophen at 1 g/kg caused damage to the centrilobular regions of the liver and increase in serum alanine and aspartate transaminase (ALT and AST, respectively) levels accompanied by elevated plasma NOx levels after 24 h. Oral administration of ONO-1714 at 10 and 100 microg/kg dose-dependently reduced the acetaminophen-induced hepatic tissue damage and the increases in serum ALT and AST levels. ONO-1714 also blocked the increase in plasma NOx concentrations. These findings demonstrate that oral ONO-1714, an iNOS inhibitor, protects against acetaminophen-evoked hepatic inflammation/injury, strongly suggesting that NO produced by iNOS plays a key role in the pathogenesis of this drug-induced hepatotoxicity.
Kamanaka
Yoshihisa
Y
Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan.
Kawabata
Atsufumi
A
Matsuya
Hidekazu
H
Taga
Chiyomi
C
Sekiguchi
Fumiko
F
Kawao
Naoyuki
N
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000578:Amidines / Q000008:administration & dosage / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009336:Necrosis; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D000082:Acetaminophen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase