α1‐Adrenoceptor antagonists prevent paracetamol‐induced hepatotoxicity in mice

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Abstract
Background and purpose: Paracetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical‐induced hepatotoxicity. We investigated the role of endogenous catecholamines and α1‐adrenoceptors in the development of paracetamol‐ induced hepatotoxicity.Experimental approach: Paracetamol (3.5 mmol kg−1) was administered to male CD‐1 mice, with and without α1‐adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 μmol kg−1). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed.Key results: Plasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol‐induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol‐induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation.Conclusion and implications: Paracetamol‐induced hepatocellular damage is associated with increased circulating catecholamines. α1‐Adrenoceptor antagonists conferred complete protection from paracetamol ‐induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol‐induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by α1antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.British Journal of Pharmacology(2008)153, 820–830; doi:10.1038/sj.bjp.0707620; published online 10 December 2007