Abstract
Few data are available in the literature regarding the effect of pentosan polysulfate (PPS) on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4) has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1) hepatic fibrosis induction with CCl4 (N = 36 rats); 2) evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats); 3) evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats); 4) evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats) using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days) male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36) developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8) and 1 mg/kg PPS (N = 8) 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45). PPS (40 mg/kg) alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks). This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.
Highlights
Carbon tetrachloride (CCl4) is a potent hepatotoxic agent often used to induce hepatic lesions, as well as to evaluate the effects of drugs on the liver
The development of liver fibrosis involves expression of cellular receptors for several growth factors that stimulate the proliferation of activated lipocytes and the synthesis of extracellular matrix [2,3,4]
Fibrosis degrees 1 and 2 were more frequent before week 6 (P
Summary
Carbon tetrachloride (CCl4) is a potent hepatotoxic agent often used to induce hepatic lesions, as well as to evaluate the effects of drugs on the liver. Short-term administration of CCl4 causes acute hepatocellular injury with centrolobular necrosis and steatosis. Chronic administration may lead to cirrhosis (liver fibrosis) [1]. The time to onset of experimental cirrhosis depends on species, route of administration, dose, interval between doses, and use of enzymatic inducers. The development of liver fibrosis involves expression of cellular receptors for several growth factors that stimulate the proliferation of activated lipocytes and the synthesis of extracellular matrix [2,3,4]. The modulation of cytokines may be a promising approach due to their action on fibrogenesis and on lipocyte proliferation [4,5,7]
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