Cyclooxygenase-2 (COX-2) expression and prostaglandin production are suggested to play important, complex roles in the pathogenesis of various liver diseases. Studies on the effects of COX-2 inhibitors on the progression of liver fibrosis present controversial results, and the proposed therapeutic potential of these agents in chronic liver disease is predicated largely on their effectiveness in modulating hepatic stellate cell activation in vitro. This study investigated the modulatory effect of celecoxib, a selective COX-2 inhibitor, in CCl(4)-mediated hepatotoxicity in rats. Thirty Wistar albino rats, weighing 120-180 g, were assigned into five groups of 6 rats/group. Groups 1 and 2 received saline (10 mL/kg) and CCl(4) (80 mg/kg), respectively. Group 3 was given celecoxib (5.7 mg/kg), whereas groups 4 and 5 were pretreated with 2.9 and 5.7 mg/kg/day of celecoxib, respectively, 1 hour before CCl(4) treatment. Plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities increased significantly by 118.5, 150.0, and 51.3%, respectively, with an accompanying decrease (P < 0.05) in total protein and albumin after CCl(4) treatment. Hepatotoxicity was associated with a significant increase in plasma cholesterol, hepatic lipid peroxidation (LPO), and severe hepatic necrosis with marked fatty and cellular (i.e., mononuclear cells) infiltration. Although celecoxib neither reduced CCl(4)-induced increases in marker enzymes of hepatotoxicity nor significantly attenuated hepatic necrosis, it, however, was effective in reducing elevated cholesterol by 16.5 and 20.8% and LPO by 12.9 and 35.5% at 2.9 and 5.7 mg/kg, respectively. Data suggest that COX-2 inhibitors may be effective in controlling hypercholesterolemia and peroxidative changes associated with liver injury.

The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl4-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1–4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl4 (80 mg/kg), respectively. Groups 5–8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl4 administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly ( p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight ( p < 0.05) in the CCl4-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly ( p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly ( p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl4 treatment. Although both drugs did not significantly alter serum biochemistry in the CCl4-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction.

These preliminary data suggest that pharmacological inhibition of PDE isozymes may be a useful strategy in protecting against PCM hepatic toxicity.

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