Abstract
The elucidation of the pathobiological events in chronic liver diseases — such as cellular injury, cell proliferation, remodelling of extracellular matrix — has considerable importance for establishing the rational bases of hepatopharmacology. To follow this concept, the molecular—pathological features of chemically induced liver damage in rats were characterized and modulated by potential hepatopharmacological compounds. Among the 55 chemical compounds tested, acute liver damage could be most effectively abolished by prostacyclin (PGI2). In addition, prostacyclins were also able to prevent cirrhosis in experimental animals. The modes of action of the prostacyclins were investigated in shortterm hepatocyte culture. The hepatotoxin-induced metabolic alterations (reduced gluconeogenesis and protein synthesis, lipid peroxidation, etc.) could be restored by prostacyclin. It was shown that PGI2 could circumvent the augmented catabolic rate of 4,5-phosphatidyl inositol-diphosphate (PIP2) in CCl4-induced hepatocyte injury. In addition, the increased intracellular calcium concentration in the injured cells was also normalized by PGI2. Thus, PIP2 metabolism appears to be a critical process in the mechanism of hepatocyte damage and its protection. Interestingly, PGI2 was effective at an advanced stage of liver injury, whereas thiazolidines were only active when administered before the application of the hepatotoxic agent. The formation of collagen could be reduced by amino-imidazolcarboxamide and silymarin. The increase in glycosaminoglycans could be abolished by the application of 5-heхyl-2deoxyuridine. The presented data provide further evidence that compounds with various targets are required in hepatopharmacology.
hepatopharmacological agents, prostacyclin
Correspondence
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References
Perrisond D, Testa B. Hepatic pharmacology mechanism of action and classification of antinecrotic hepatoprotective agents. Trends Pharmacol Sci. 1982; 3: 365–7.
Szepesházy K, Lapis K, Jeney A et al. Morphological and biochemical studies on the effect of agents with liver protecting properties. Exp Pathol. 1978; 15: 271–87.
Ujhelyi E, Divald A, Vajta G, Jeney A, Lapis K. Effect of PGI2 in carbon tetrachloride induced liver injury. Acta Physiol Hung. 1984; 64: 425–30.
Jeney A, Divald A, Szende B et al. Hepatoprotective action of prostacyclin and its possible mechanisms. In: Kecskeméti V, Gyires K, Kovács G. Proceedings of the 4th Congress of Hungarian Pharmacology Society, Budapest, 1985:503–59.
Lapis K, Jeney A, Divald A, Vajta G, Zalatnai A, Schaff Zs. Experimental studies on the effect of hepatoprotective compounds. Tokai J Exp Clin Med. 1986; 14 (Suppl.): 135–45.
Kovács G, Simonidesz V, Tömösközi Petal. A new stable prostacyclin mimic, 7-oxoprostaglandin I2. J Med Chem. 1982; 25: 105–7.
Seglen PO. Preparation of isolated rat liver cells. Meth Cell Biol. 1976; 13: 29–83.
Vajta G, Divald A, Elek J, Paku S, Lapis K. Fatty degeneration in cultured hepatocytes–a new experimental model. Virchows Arch B Cell Pathol. 1986; 52: 177–84.
Divald A, Jeney A, O-Nagy J, Timáеr F, Lapis K. Modification of the inhibitory effects of CC14 on phospholipid and protein biosynthesis by prostacyclin. Biochem Pharmacol. 1990; 40: 1477–83.
Divald A, Vajta G, Oláh 3, Jeney A, Lapis K. Effect of prostacyclin on the triglyceride catabolism in CC14 poisoned hepatocytes. IRCS Med Sci (Biochem). 1985; 13: 1117–18.
Reitman S, Frankel S. A colorimetric method for the determination of serum oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 1977; 28: 56–63.
Biggs HG, Erikson JM, Moorehead WR. A manual colorimetric assay of triglycerides in serum. Clin Chem. 1975; 21: 437–41.
Morris DL. Quantitative determination of carbohydrates with Dreywood’s anthron reagent. Science. 1948; 107: 254.
Divald A, Ujhelyi E, Jeney A, Lapis K, Institoris L. Hepatoprotective effects of prostacyclin on CCl4induced liver injury in rats. Exp Mol Pathol. 1985; 42: 163–6.
Ujhelyi E, Kovács L, Szepesházi K, Jeney A, Lapis K. Morphological and biochemical study of the hepatoprotective effect of AICA phosphate. Acta Med Acad Sci Hung. 1980; 37: 99–103.
Kovalszky I, Рogány G, Molnár G et al. Altered glycosaminoglycan composition in reactive and neoplastic human liver. Biochem Biophys Res Commun. 1990; 167: 883–90.
Lamb RG, Schwertz DW. The effect of bromobenzene and carbon tetrachloride exposure in vitro on phospholipase C activity of rat liver cells. Toxicol Appl Pharmacol. 1982; 65: 216–29.
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© 1997 Springer Science+Business Media Dordrecht
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Jeney, A. et al. (1997). Modification of Pathobiological Events by Potential Hepatopharmacological Agents. In: Gaginella, T.S., Mózsik, G., Rainsford, K.D. (eds) Biochemical Pharmacology as an Approach to Gastrointestinal Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-5390-4_29
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DOI: https://doi.org/10.1007/978-94-011-5390-4_29
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