Inhibition of Matrix Metalloproteinases Minimizes Hepatic Microvascular Injury in Response to Acetaminophen in Mice

• Published in: Toxicological sciences 2005-01, Vol.83 (1), p.190-196
• Main Authors: Ito, Yoshiya, Abril, Edward R., Bethea, Nancy W., McCuskey, Robert S.
• Format: Article
• Language: English
• Subjects: Acetaminophen - toxicity; Administration, Oral; Animals; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - pathology; Enzyme Inhibitors - pharmacology; Glutathione - metabolism; hemorrhage; Hemorrhage - enzymology; Hemorrhage - pathology; hepatotoxicity; Liver - blood supply; Liver - drug effects; Liver - enzymology; Liver - pathology; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - biosynthesis; Mice; Mice, Inbred C57BL; microcirculation; Microcirculation - drug effects; Microcirculation - enzymology; Microcirculation - pathology; Necrosis; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; sinusoidal endothelial cells; Sulfonamides - pharmacology
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfh291

The acetaminophen (APAP)-induced hepatic centrilobular necrosis is preceded by hepatic microcirculatory dysfunction including the infiltration of erythrocytes into the space of Disse. The purpose of this study was to examine the involvement of matrix metalloproteinases (MMPs) in the hepatic microvascular injury elicied by APAP. Male C57Bl/6 mice were pretreated with 2-[(4-biphenylsulfonyl) amino]-3-phenyl-propionic acid, an MMP-2/MMP-9 inhibitor (5 mg/kg, ip) 30 min before oral gavage with 600 mg/kg of APAP. The hepatic microvasculature in anesthetized mice was observed using established in vivo microscopic methods 2 and 6 h after APAP. The levels of mRNAs and activities of MMP-2 and MMP-9 in the liver were increased from 1 h through 6 h after APAP gavage. APAP increased alanine transferase (ALT) levels (41.1-fold) and resulted in centrilobular hemorrhagic necrosis at 6 h. Pretreatment with 2-[(4-biphenylsulfonyl) amino]-3-phenyl-propionic acid attenuated ALT values by 71% as well as the necrosis. APAP decreased the numbers of perfused sinusoids in centrilobular regions by 30% and increased the area occupied by infiltrated erythrocytes into Disse space. 2-[(4-Biphenylsulfonyl) amino]-3-phenyl-propionic acid restored the sinusoidal perfusion to 90% of control levels and minimized extrasinusoidal area occupied by erythrocytes. The present study showed that increased MMPs during APAP intoxication are associated with hepatocellular damage and with hepatic microcirculatory dysfunction including impaired sinusoidal perfusion and infiltration of erythrocytes in Disse space. 2-[(4-Biphenylsulfonyl) amino]-3-phenyl-propionic acid attenuated APAP-induced parenchymal and microvascular injury. These results suggest that MMPs participate in APAP hepatotoxicity mediated by sinusoidal endothelial cell injury, which results in impairment of microcirculation.