Digestive Diseases and Sciences

, Volume 39, Issue 6, pp 1249–1256 | Cite as

Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat

  • S. Ping Lim
  • Fiona J. Andrews
  • Paul E. O'Brien
Original Articles


The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448±48 µg/g to 82±2 µg/g (P<0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454±446 IU/liter and 2571±2944 IU/liter, respectively) compared to those without misoprostol treatment (1348±480 IU/liter and 6077±3025 IU/liter, respectively,P<0.01). TNBT staining showed a reduced area of damage from 28.6±22.3% to 7.3±8.9% (P<0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose. Late administration of misoprostol may also be beneficial and thus may be considered in treating patients with APAP toxicity.

Key words

acetaminophen hepatotoxicity misoprostol hepatoprotection 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rush BD, Wilkinson KF, Nichols NM, Ochoa R, Brunden MN, Ruwart MJ: Hepatic protection by 16,16-dimethyl prostaglandin E2 (DMPG) against acute aflatoxin B1-induced injury in the rat. Prostaglandins 37:683–693, 1989Google Scholar
  2. 2.
    Bursch W, Taper HS, Somer MP, Meyer S, Putz B, Schulte-Hermann R: Histochemical and biochemical studies on the effect of the prostacyclin derivative Iloprost on CCl4-induced lipid peroxidation in rat liver and its significance for hepatoprotection. Hepatology 9:830–838, 1989Google Scholar
  3. 3.
    Levine RA: Hepatic cytoprotection by prostaglandins: Theories unlimited. Hepatology 8:969–970, 1988Google Scholar
  4. 4.
    Araki H, Lefer AM: Cytoprotective actions of prostacyclin during hypoxia in the isolated perfused cat liver. Am J Physiol 238:H176-H181, 1980Google Scholar
  5. 5.
    Alvarez-Lopez A, de Hemptinne B, Hoebeke Y, Lambotte L: Prostaglandin E2 increases the tolerance of the rat liver to warm ischemia in absence of splanchnic congestion. Transplant Proc 19:4105–4109, 1987Google Scholar
  6. 6.
    Lim SP, Andrews FJ, Christophi C, O'Brien PE: Misoprestol hepatoprotection against ischemia-reperfusion-induced liver injury in the rat. Dig Dis Sci 37:1275–1281, 1992Google Scholar
  7. 7.
    Stachura J, Tarnawski A, Szczudrawa J, Bogdal J, Mach T, Barbara K, Kirchmayer S: Cytoprotective effect of 16,16-dimethyl prostaglandin E2 and some drugs on an acute galactosamine induced liver damage in rat. Folia Histochem Cytochem 18:311–318, 1980Google Scholar
  8. 8.
    Bursch W, Schulte-Hermann R: Cytoprotective effect of the prostacyclin derivative iloprost against liver cell death induced by the hepatotoxins carbon tetrachloride and bromobenzene. Klin Wochenschr 64(suppl VII):47'50, 1986Google Scholar
  9. 9.
    Stachura J, Tarnawski A, Ivey KJ, Mach T, Bogdal J, Szczudrawa J, Klimczyk B: Prostaglandin protection of carbon tetrachloride-induced liver cell necrosis in the rat. Gastroenterology 81:211–217, 1981Google Scholar
  10. 10.
    Ruwart MJ, Rush BD, Friedle NM, Piper RC, Kolaja GJ: Protective effects of 16,16-dimethyl PGE2 on the liver and kidney. Prostaglandins 21(suppl):97–102, 1981Google Scholar
  11. 11.
    Guarner F, Boughton-Smith NK, Blackwell GJ: Reduction by prostacyclin of acetaminophen induced liver toxicity in the mouse. Hepatology 8:248–253, 1988Google Scholar
  12. 12.
    Raheja KL, Linscheer WG, Cho CD, Coulson R: Failure of exogenous prostaglandin to afford complete protection against acetaminophen-induced hepatotoxicity in the rat. J Toxicol Environ Health 15:477–484, 1985Google Scholar
  13. 13.
    Nasseri-Sina P, Fawthrop DJ, Wilson J, Boobis AR, Davis DS: Cytoprotection by iloprost against paracetamol-induced toxicity in Hamster isolated hepatocytes. Br J Pharmacol 105:417–423, 1992Google Scholar
  14. 14.
    Misoprostol (Cytotec). Preclinical and clinical review. Glenview, Illinois, Physicians and Scientists Publishing, 1990Google Scholar
  15. 15.
    Ohshita M, Takeda H, Kamiyama Y, Ozawa K, Honjo I: A direct method for the estimation of ornithine carbamoyl-transferase activity in serum. Clin Chim Acta 67:145–152, 1976Google Scholar
  16. 16.
    Reitman S, Frankel S: A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63, 1957Google Scholar
  17. 17.
    Frederiks WM, Fronik GM, Hesseling JMG: A method for quantitative analysis of the extent of necrosis in ischemic rat liver. Exp Mol Pathol 41:119–125, 1984Google Scholar
  18. 18.
    Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB: Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 187:185–194 1973Google Scholar
  19. 19.
    Hissin PJ, Hilf R: A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226, 1976Google Scholar
  20. 20.
    Davis M, Simmons CJ, Harrison NG, Williams R: Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage. Q J Med 45:181–191, 1976Google Scholar
  21. 21.
    Davis M: Protective agents for acetaminophen overdose. Semin Liver Dis 6:138–147, 1986Google Scholar
  22. 22.
    Mant TGK, Tempowski JH, Volans GN, Talbot JCC: Adverse reactions to acetylcysteine and effects of overdose. Br Med J 289:217–219, 1984Google Scholar
  23. 23.
    Walker RM, Racz WJ, McElligott TF: Scanning electron microscopic examination of acetaminophen-induced hepatotoxicity and congestion in mice. Am J Pathol 113:321–330, 1983Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • S. Ping Lim
    • 1
  • Fiona J. Andrews
    • 1
  • Paul E. O'Brien
    • 1
  1. 1.From the Department of SurgeryMonash Medical School, Alfred HospitalPrahranAustralia

Personalised recommendations