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. 1992 Feb;105(2):417–423. doi: 10.1111/j.1476-5381.1992.tb14268.x

Cytoprotection by iloprost against paracetamol-induced toxicity in hamster isolated hepatocytes.

P Nasseri-Sina 1, D J Fawthrop 1, J Wilson 1, A R Boobis 1, D S Davies 1
PMCID: PMC1908660  PMID: 1373102

Abstract

1 The ability of iloprost (ZK36374) to protect hamster isolated hepatocytes from the toxic effects of paracetamol and its reactive metabolite N-acetyl-p-benzoquinoneimine (NABQI) was investigated. The cytoprotection provided by iloprost was compared with that of N-acetyl-L-cysteine. 2 Treatment of hepatocytes with either NABQI (0.4 mM) or paracetamol (2 mM) alone resulted in a considerable loss of cell viability, as assessed by trypan blue exclusion or leakage of lactate dehydrogenase, accompanied by an increase in the percentage of viable cells that were blebbed. N-acetyl-L-cysteine (1.25 mM) pretreatment diminished the loss of cell viability and the percentage of blebbed cells resulting from exposure to NABQI or paracetamol, whereas iloprost (10(-16) M to 10(-10) M) pretreatment reduced only the loss of cell viability, not the percentage of viable cells exhibiting blebbing. Pretreatment with N-acetyl-L-cysteine significantly attenuated the depletion by paracetamol of glutathione and decreased the covalent binding of [14C]-paracetamol to cellular proteins, whereas iloprost was without any such effects. 3 The effects of iloprost and N-acetyl-L-cysteine were also investigated by use of a model of paracetamol toxicity in which it is possible to study the biochemical events leading to cell injury separate from the generation of toxic metabolites. Hamster hepatocytes were incubated with paracetamol (4 mM) for 90 min at 37 degrees C during which metabolism of paracetamol occurs with minimal loss of cell viability.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Akerboom T. P., Sies H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol. 1981;77:373–382. doi: 10.1016/s0076-6879(81)77050-2. [DOI] [PubMed] [Google Scholar]
  2. Araki H., Lefer A. M. Cytoprotective actions of prostacyclin during hypoxia in the isolated perfused cat liver. Am J Physiol. 1980 Feb;238(2):H176–H181. doi: 10.1152/ajpheart.1980.238.2.H176. [DOI] [PubMed] [Google Scholar]
  3. Boobis A. R., Fawthrop D. J., Davies D. S. Mechanisms of cell death. Trends Pharmacol Sci. 1989 Jul;10(7):275–280. doi: 10.1016/0165-6147(89)90027-8. [DOI] [PubMed] [Google Scholar]
  4. Bruno M. K., Cohen S. D., Khairallah E. A. Antidotal effectiveness of N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity. Enhancement of the proteolysis of arylated proteins. Biochem Pharmacol. 1988 Nov 15;37(22):4319–4325. doi: 10.1016/0006-2952(88)90613-2. [DOI] [PubMed] [Google Scholar]
  5. 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. 1986;64 (Suppl 7):47–50. [PubMed] [Google Scholar]
  6. Bursch W., Taper H. S., Somer M. P., 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. 1989 Jun;9(6):830–838. doi: 10.1002/hep.1840090607. [DOI] [PubMed] [Google Scholar]
  7. Chaudhury T. K., Jacobson E. D. Prostaglandin cytoprotection of gastric mucosa. Gastroenterology. 1978 Jan;74(1):58–63. [PubMed] [Google Scholar]
  8. Ferrari R., Cargnoni A., Curello S., Boffa G. M., Ceconi C. Effects of iloprost (ZK 36374) on glutathione status during ischaemia and reperfusion of rabbit isolated hearts. Br J Pharmacol. 1989 Oct;98(2):678–684. doi: 10.1111/j.1476-5381.1989.tb12643.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Funck-Brentano C., Tinel M., Degott C., Letteron P., Babany G., Pessayre D. Protective effect of 16,16-dimethyl prostaglandin E2 on the hepatotoxicity of bromobenzene in mice. Biochem Pharmacol. 1984 Jan 1;33(1):89–96. doi: 10.1016/0006-2952(84)90374-5. [DOI] [PubMed] [Google Scholar]
  10. Guarner F., Boughton-Smith N. K., Blackwell G. J., Moncada S. Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse. Hepatology. 1988 Mar-Apr;8(2):248–253. doi: 10.1002/hep.1840080210. [DOI] [PubMed] [Google Scholar]
  11. Guarner F., Fremont-Smith M., Prieto J. Cytoprotective effect of prostaglandins on isolated rat liver cells. Liver. 1985 Feb;5(1):35–39. doi: 10.1111/j.1600-0676.1985.tb00013.x. [DOI] [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Lancaster C., Robert A. Intestinal lesions produced by prednisolone: prevention (cytoprotection) by 16,16-dimethyl prostaglandin E2. Am J Physiol. 1978 Dec;235(6):E703–E708. doi: 10.1152/ajpendo.1978.235.6.E703. [DOI] [PubMed] [Google Scholar]
  14. Lefer A. M., Ogletree M. L., Smith J. B., Silver M. J., Nicolaou K. C., Barnette W. E., Gasic G. P. Prostacyclin: a potentially valuable agent for preserving myocardial tissue in acute myocardial ischemia. Science. 1978 Apr 7;200(4337):52–54. doi: 10.1126/science.345441. [DOI] [PubMed] [Google Scholar]
  15. Lombroso M., Nicosia S., Paoletti R., Whittle B. J., Moncada S., Vane J. R. The use of stable prostaglandins to investigate prostacyclin (PGI2)-binding sites and PGI2-sensitive adenylate cyclase in human platelet membranes. Prostaglandins. 1984 Feb;27(2):321–333. doi: 10.1016/0090-6980(84)90083-2. [DOI] [PubMed] [Google Scholar]
  16. Manabe T., Steer M. L. Protective effects of PGE2 on diet-induced acute pancreatitis in mice. Gastroenterology. 1980 Apr;78(4):777–781. [PubMed] [Google Scholar]
  17. Mihas A. A., Markov A. K., Subramony C. Protective effects of misoprostol on carbon tetrachloride-induced liver damage in the rat. Pharmacology. 1991;42(5):283–286. doi: 10.1159/000138809. [DOI] [PubMed] [Google Scholar]
  18. Noda Y., Hughes R. D., Williams R. Effect of prostacyclin (PGI2) and a prostaglandin analogue BW 245C on galactosamine-induced hepatic necrosis. J Hepatol. 1986;2(1):53–64. doi: 10.1016/s0168-8278(86)80008-3. [DOI] [PubMed] [Google Scholar]
  19. Papanicolaou N., Callard P., Bariety J., Milliez P. The effect of indomethacin and prostaglandin (PGE2) on renal failure due to glycerol in saline-loaded rats. Clin Sci Mol Med. 1975 Nov;49(5):507–510. doi: 10.1042/cs0490507. [DOI] [PubMed] [Google Scholar]
  20. Robert A. Antisecretory, antiulcer, cytoprotective and diarrheogenic properties of prostaglandins. Adv Prostaglandin Thromboxane Res. 1976;2:507–520. [PubMed] [Google Scholar]
  21. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979 Oct;77(4 Pt 1):761–767. [PubMed] [Google Scholar]
  22. Robert A., Nezamis J. E., Lancaster C., Hanchar A. J. Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology. 1979 Sep;77(3):433–443. [PubMed] [Google Scholar]
  23. Robert A., Nezamis J. E., Phillips J. P. Effect of prostaglandin E1 on gastric secretion and ulcer formation in the rat. Gastroenterology. 1968 Oct;55(4):481–487. [PubMed] [Google Scholar]
  24. Rush B. D., Wilkinson K. F., Nichols N. M., Ochoa R., Brunden M. N., Ruwart M. J. Hepatic protection by 16, 16-dimethyl prostaglandin E2 (DMPG) against acute aflatoxin B1-induced injury in the rat. Prostaglandins. 1989 Jun;37(6):683–693. doi: 10.1016/0090-6980(89)90105-6. [DOI] [PubMed] [Google Scholar]
  25. Ruwart M. J., Rush B. D., Friedle N. M., Piper R. C., Kolaja G. J. Protective effects of 16,16-dimethyl PGE2 on the liver and kidney. Prostaglandins. 1981;21 (Suppl):97–102. doi: 10.1016/0090-6980(81)90124-6. [DOI] [PubMed] [Google Scholar]
  26. Schrör K., Darius H., Matzky R., Ohlendorf R. The antiplatelet and cardiovascular actions of a new carbacyclin derivative (ZK 36 374)--equipotent to PGI2 in vitro. Naunyn Schmiedebergs Arch Pharmacol. 1981 Jun;316(3):252–255. doi: 10.1007/BF00505658. [DOI] [PubMed] [Google Scholar]
  27. Stachura J., Tarnawski A., Ivey K. J., Mach T., Bogdal J., Szczudrawa J., klimczyk B. Prostaglandin protection of carbon tetrachloride-induced liver cell necrosis in the rat. Gastroenterology. 1981 Aug;81(2):211–217. [PubMed] [Google Scholar]
  28. Stachura J., Tarnawski A., Szczudrawa J., Bogdał J., Mach T., Klimczyk B., 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 (Krakow) 1980;18(4):311–317. [PubMed] [Google Scholar]
  29. Tee L. B., Boobis A. R., Huggett A. C., Davies D. S. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol. 1986 Apr;83(2):294–314. doi: 10.1016/0041-008x(86)90307-8. [DOI] [PubMed] [Google Scholar]
  30. Tee L. B., Davies D. S., Seddon C. E., Boobis A. R. Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite. Biochem Pharmacol. 1987 Apr 1;36(7):1041–1052. doi: 10.1016/0006-2952(87)90412-6. [DOI] [PubMed] [Google Scholar]
  31. Tee L. B., Seddon T., Boobis A. R., Davies D. S. Drug metabolising activity of freshly isolated human hepatocytes. Br J Clin Pharmacol. 1985 Mar;19(3):279–294. doi: 10.1111/j.1365-2125.1985.tb02645.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ujhelyi E., Divald A., Vajta G., Jeney A., Lapis K. Effect of PGI2 in carbon tetrachloride-induced liver injury. Acta Physiol Hung. 1984;64(3-4):425–430. [PubMed] [Google Scholar]

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