Acetaminophen-induced microvascular injury in the rat liver: Protection with misoprostol

✍ Scribed by Sook Ping Lim; Fiona Jane Andrews; Paul Edmond O'Brien

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 932 KB
• Volume: 22
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840220625

✦ Synopsis

Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mgkg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin El analog) treatment (6 x 25 p&g) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with AF'AP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level. (HEPATOLOGY 1995;22:1776-1781.) Acetaminophen (APAP) is a widely used analgesic and antipyretic agent. In normal therapeutic doses, APAP is considered a safe drug. However, fulminant hepatic necrosis has been reported in and experimental animal^^.^ after overdose with APAP.