Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: Mechanistic studies

This study was designed to elucidate the mechanism of retinol's potentiatio n of acetaminophen-induced hepatotoxicity. To accomplish this, the major bi oactivation and detoxification pathways for acetaminophen were investigated following retinol (75 mg/kg/day, 4 days), acetaminophen (400 mg/kg), and r etinol + acetaminophen treatment. Hepatic microsomes were used to determine the catalytic activity and polypeptide levels of cytochrome P450 enzymes i nvolved in the murine metabolism of acetaminophen. Results showed that the catalytic activity and polypeptide levels of CYP1A2, CYP2E1, and CYP3A were unchanged in the treatment groups compared to vehicle and untreated contro ls. In combination, retinol + acetaminophen caused a significantly greater depletion of GSH compared to corn oil + acetaminophen (0.36 +/- 0.11 vs 0.8 9 +/- 0.19 mu mol/g, respectively, p < 0.05). This greater GSH depletion co rrelated with a higher degree of hepatic injury in the retinol + acetaminop hen-treated animals but is probably not the cause of the potentiated injury since the results showed that retinol treatment itself did not alter hepat ic glutathione (3.34 +/- 0.43 vs 3.44 +/- 0.46 <mu>mol/g for retinol vs veh icle, respectively). However, hepatic UDPGA stores were decreased in the re tinol-treated group compared to untreated and corn oil controls (54.6 +/- 1 0.6 vs 200.6 +/- 17.6 nmol/g for retinol and untreated control, respectivel y, p < 0.001). This demonstrates that there is significantly less hepatic U DPGA available for conjugation following retinol administration. The result s suggest that decreased hepatic UDPGA is likely the cause of retinol's pot entiation of acetaminophen-induced hepatic injury. (C) 2001 Academic Press.