Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats

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 (CCl 4 ) 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 CCl 4 for the induction of liver fibrosis. The study consisted of four stages: 1) hepatic fibrosis induction with CCl 4 (N = 36 rats); 2) evaluation of the effect of PPS on CCl 4 -induced hepatic fibrosis (N = 36 rats); 3) evaluation of the effect of higher doses of PPS in combination with CCl 4 (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% CCl 4 (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 CCl 4 , 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 CCl 4 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 CCl 4 and high doses of PPS, which results in massive hepatic necrosis.

Inhibitory effects of salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBα signaling

“…A single dose of CCl 4 causes acute hepatocellular injury with centrizonal necrosis and steatosis, while prolonged administration may lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma (Zim et al, 2002), which have been thought to result from the formation of reactive intermediates such as trichloromethyl free radicals (CCl 3 þ ) metabolized by the mixed function cytochrome p450 in the endoplasmic reticulum (Huo et al, 2011). CCl 4 impairs hepatocytes directly by altering the permeability of the plasma, lysosomal, and mitochondrial membranes (Fujii et al, 2010).…”

Potency of Methanolic Extract of <I>Zizyphus jujuba</I> Fruit against Carbontetrachloride Induced Hepatic Damage in Rats

“…Short-term administration of CCl 4 causes acute hepatocellular injury with centrolobular necrosis and steatosis. Chronic administration may lead to cirrhosis (liver fibrosis) 19 . CCl 4 is catalyzed by cytochrome P450 enzyme and forms the highly reactive trichloromethyl free radical.…”

<b>Modelos experimentais para indução de cirrose hepática em animais: Revisão de literatura</b><br>doi: 10.5007/2175-7925.2010v23n2p183

“…Em uma visão geral, considera-se como vantagem na indução por CCl 4 sua correlação com a cirrose hepática em relação às questões morfofisiopatológicas, como a insuficiência hepática obtida (Zim et al, 2002;Natarajan et al, 2006). Entretanto, desvantagens, como a presença de septos fibrosos, pouca proliferação ductobiliar e rápida regressão das lesões dificultam o estudo de tratamentos anticirróticos em longo prazo (Cremonese et al, 2001;Li et al, 2002;Muriel e Escobar, 2003), devido à baixa reprodutibilidade e homogeneidade do quadro cirrótico (Laleman et al, 2006) e alto índice de mortalidade encontrados durante a indução (Jeong et al, 2001;Li et al, 2002;Laleman et al, 2006;Lee et al, 2008).…”