Acetaminophen hepatotoxicity: Is there a role for prostaglandin synthesis?

Abstract

The hepatotoxicity of acetaminophen (APAP) overdose depends on metabolic activation to a toxic reactive metabolite via hepatic mixed function oxidase. In vitro studies have indicated that APAP may also be cooxidized by prostaglandin H synthetase. The present experiments were designed to assess the possible contribution of hepatic prostaglandin synthesis to APAP toxicity. Adult fed male mice were overdosed with 400 mg APAP/kg. Liver toxicity was estimated by measurement of serum transaminases. Hypertonic xylitol or sodium chloride (2250 mOsm/l), administered intragastrically to stimulate prostaglandin synthesis, increased APAP toxicity. By contrast, the cyclooxygenase inhibiting drugs aspirin (at 25 mg/kg) and indomethacin (at 10 mg/kg) protected against APAP-induced toxicity. APAP kinetics were not affected by hypertonic xylitol or indomethacin, nor were hepatic glutathione levels in overdosed mice. Imidazole, a nonspecific thromboxane synthetase inhibitor, also protected overdosed mice. This drug prolonged hexobarbital sleeping time and prevented the depletion of hepatic glutathione that followed APAP intoxication. Thus, the data support the conclusion that APAP-induced hepatoxicity may be modulated not only by inhibition of cytochrome P450 mediated oxidation, but also by controlling hepatic cyclooxygenase activity.

Induction of Hepatic Transporters Multidrug Resistance-Associated Proteins (Mrp) 3 and 4 by Clofibrate Is Regulated by Peroxisome Proliferator-Activated Receptor α

“…Modulation of inflammatory mediators such as prostaglandins and eicosanoids are associated with alterations in the severity of acetaminophen toxicity (Ben-Zvi et al, 1990;Culo et al, 1995). Altered disposition of these inflammatory mediators by hepatic efflux transporters may provide a mechanism for hepatoprotection.…”

Concomitant overdosing of other drugs in patients with paracetamol poisoning

“…Increased hepatic prostaglandin synthesis has been suggested as a mediator of paracetamol hepatotoxicity at a stage subsequent to toxic metabolite formation [12,20]. Consequently, the inhibition of cyclooxygenase by ASA and NSAID may protect against paracetamol-induced hepatotoxicity [20].…”

“…However, the serum concentrations of ASA were only moderate (1.3, 2.0, 0.8, and 1.7 mmol l x1 , respectively), and well below the Danish recommended treatment threshold of 3.6 mmol l x1 . 25 Time to NAC (h) 16 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] 17 19 16 14 17 8 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] 17 Chronic alcohol 34 (34%) 132 (23%) Concomitant NSAID overdose showed a tendency towards a less severe outcome and was marginally significant as a protective factor in the development of HE (OR 0.14 (0.01, 1.36); P=0.08). In particular, no sign of increased risk of renal failure was observed.…”

“…In a substantial proportion of cases, the patient has concomitantly overdosed one or more other drugs in addition to paracetamol [2,3,6,7]. Such drugs may affect the outcome of the paracetamol intoxication as a result of pharmacokinetic interaction with paracetamol or through independent toxic or hepato-protective properties [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Drug interactions with paracetamol may lead to reduced as well as enhanced hepatotoxicity.…”

“…Suggested mechanisms of interaction include an increased or reduced rate of absorption of paracetamol, reduced conjugation of paracetamol, depletion of glutathione, and inhibition of cytochrome P450-mediated metabolism [9][10][11][12][13][14][15][16]. Independent hepatoprotective mechanisms may involve antioxidant, membrane stabilizing, or calcium channel blocking properties of drugs [17][18][19][20][21]. Thus, the same drug may have several and even opposing effects on the paracetamol intoxication [22].…”