alpha(1)-Adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice.
OBJECTIVE
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 alpha(1)-adrenoceptors in the development of paracetamol- induced hepatotoxicity.


METHODS
Paracetamol (3.5 mmol kg(-1)) was administered to male CD-1 mice, with and without alpha(1)-adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 micromol 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.


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.


CONCLUSIONS
Paracetamol-induced hepatocellular damage is associated with increased circulating catecholamines. alpha(1)-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 alpha(1) antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.
Randle
L E
LE
Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, UK.
Sathish
J G
JG
Kitteringham
N R
NR
Macdonald
I
I
Williams
D P
DP
Park
B K
BK
D000082:Acetaminophen / Q000378:metabolism; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002395:Catecholamines / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D017292:Doxazosin / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D013997:Time Factors; D000637:Transaminases / Q000097:blood
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D008565:Membrane Proteins; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D000082:Acetaminophen; C041226:Terazosin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000637:Transaminases; D005721:Glutamate-Cysteine Ligase; D000077409:Tamsulosin; D005978:Glutathione; D017292:Doxazosin; D011224:Prazosin