Paracetamol-induced Liver Injury

In the field of free radicals and liver injury there is a vast body of work concerning a group of compounds that have proven to be of great value as experimental models but are of little clinical significance. The most frequently used compounds are quinones (particularly menadione), paraquat and diquat, bromobenzene, and organic hydroperoxides, particularly cumene hydroperoxide and r-butyl hydroperoxide (see Poli et al., 1989b). 

Organic peroxides such as cumene hydroperoxide and t-butyl hydroperoxide have extensively been used as experimental agents. They provoke lipid peroxidation in hepatocytes, probably by the generation of alkoxyl and peroxyl radical intermediates after reaction with cytochrome P450. Other cytotoxic mechanisms are probably involved including protein thiol and non-protein thiol oxidation and deranged calcium homeostasis (Jewell et al., 1986). In fact, the addition of cumene hydroperoxide to isolated bUe duct cells, devoid of cytochrome P450 activity, still results in cell death but lipid peroxidation is not detectable (Parola et al., 1990). 

The above studies have generated a huge body of invaluable data concerning the effects of oxidative stress on cells. In particular the importance of GSH in cell protection and the role of disturbed calcium homeostasis in cell killing have been greatly illuminated. 

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Liver Nimesulide-induced hepatotoxidty can occur, with serious and potentially fatal outcomes. Three cases of liver failure related to nimesulide have been reported 77, 78 ]. In a retrospective analysis from the Irish national liver transplant unit all recipients of a liver transplant for fulminant hepatic failure of unknown cause (1994-2007) were evaluated [79 ]. There were 32 patients with seronegative, non-paracetamol-induced liver failure. Nimesulide had been started within 6 months in six patients and was assessed as probably associated with liver injury in all of these cases. 

Ricinis communis was shown to be effective in treatment of experimental liver injury [212]. Ricinine was not found to have hepatoprotective activity [213]. /V-Demethylricinine, however, displayed dose-dependent choleretic activity, and anticholestatic and hepatoprotective activity against hepatic damage induced with paracetamol [213]. 

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