Paracetamol-induced Liver Damage

Portal infusion of NAPQl into rats and mice produces necrosis in the periportal region (unpublished results quoted by Nelson, 1990). Studies of cultured hepatocytes sensitized to paracetamol by the induction of cytochrome P450 by 3-methylcholanthrene have shown that paracetamol-induced cytotoxicity was dependent on ROM generation (Gerson et al., 1985). 

Paracetamol-induced hepatotoxicity can be prevented in animals with SOD, catalase and allopurinol (Kyle et al., 1987 Jaeschke, 1990 Tirmenstein and Nelson, 1990), and by N-acetyl-L-cysteine or methionine in humans (Meredith et al., 1986 Nelson, 1990). The protective efiect of allopurinol in mice only occurred at high concentrations, suggesting that its effect was related to scavenging of ROMs rather than inhibition of their production by XO (Jaeschke, 1990). 

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Mendoza, S., M. Noa, R. Mas, and N. Mendoza. Effect of D-003, a mixture of high molecular weight primary acids from sugar cane wax, on paracetamol-induced liver damage in rats. Int J Tissue React 2003 25(3) 91-98. 

N-acetyl-cysteine, a synthetic precursor of cysteine, is commonly used as an antidote to paracetamol-induced liver damage... 

Table 7.3 Mean Plasma Concentration and Half-Life of Unchanged Paracetamol in Patients with and Without Paracetamol-Induced Liver Damage...

Figure 7.17 Species differences in the dose-response relationship for paracetamol-induced liver damage. Source From Refs. 5 and 6.

Experience in 59 pregnant patients suggested that use of N-acetylcysteine in pregnancy did not result in toxic effects on the fetus. In practice, the risk to the mother and baby of paracetamol-induced liver damage probably far outweighs any potential risk of N-acetylcysteine, and pregnancy should not be considered a contraindication to the use of this agent. 

Benedetti MS, Louis A, Malone A, Shneider M, Lam R. 1975. Prevention of paracetamol-induced liver damage in mice with glutathione. J. Pharm. Pharmacol. 27 629-32... 

FIGURE 7.9 Species differences in the dose-response relationship for paracetamol-induced liver damage. Data from Potter et al., Pharmacology (1974) 12, 129 and Mitchell et al., J.Pharmacol. Exp. Ther. (1973) 187,185. 

Primary events. As already mentioned many compounds are toxic following metabolism to reactive metabolites. These reactive metabolites may then initiate one or more primary events. For example, paracetamol and bromobenzene-induced liver damage results from metabolic activation, discussed in more detail in Chapter 7. In other cases metabolic activation is not necessary, and the parent compound or a stable metabolite initiates the primary event. For example, cyanide is cytotoxic as a result of inhibition of crucial enzymes and carbon monoxide deprives the cell of oxygen (see Chapter 7 for more details). 

Beckett, G. J., Foster, G. R., Hussey, A. J., Oliveira, D. B.G., Donovan, J. W., Prescott, L. F., and Proudfoot, A. T., Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage. Clin. Chem. (Winston-Salem, N.C.) 35, 2186-2189 (1989). 

Muriel, R, Garciapina, T., Perez-Alvarez, V., Mourelle, M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J. y pl. Toxicol. 1992 12 439-442... 

Many case reports describe severe liver damage, sometimes fatal, in some alcoholics and persistent heavy drinkers who take only moderate doses of paracetamol. However, other controlled studies have found no association between alcoholism and paracetamol-induced hepatotoxicity. There is controversy about the use of paracetamol in alcoholics. Some consider standard therapeutic doses can be used, whereas others recommend the dose of paracetamol should be reduced, or paracetamol avoided. Occasional and light to moderate drinkers do not seem to be at any extra risk. One study found that chronic alcohol intake, bnt not acute alcohol intake, enhanced paracetamol hepatotoxicity following overdose. 

Lesna, M., Watson, A. J., Douglas, A. P., Hamlyn, A. N. and James, O. F. W. (1976) Evaluation of paracetamol-induced damage in liver biopsies. Acute changes and follow-up findings. Virchows Arch. Path. Anat., 370, 333. 

Side-effects are rare and may include hematological reactions, leucopenia, agranulocytosis and other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and overdosage induces severe liver and renal damage (Lewis and Paloucek, 1991) via accumulation of a toxic metabolite, N- acetyl-benzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase glutathione conjugation of the metabolite, are used as the antidote. 

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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