Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: mechanistic studies.
This study was designed to elucidate the mechanism of retinol's potentiation of acetaminophen-induced hepatotoxicity. To accomplish this, the major bioactivation and detoxification pathways for acetaminophen were investigated following retinol (75 mg/kg/day, 4 days), acetaminophen (400 mg/kg), and retinol + acetaminophen treatment. Hepatic microsomes were used to determine the catalytic activity and polypeptide levels of cytochrome P450 enzymes involved 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 controls. In combination, retinol + acetaminophen caused a significantly greater depletion of GSH compared to corn oil + acetaminophen (0.36 +/- 0.11 vs 0.89 +/- 0.19 micromol/g, respectively, p < 0.05). This greater GSH depletion correlated with a higher degree of hepatic injury in the retinol + acetaminophen-treated animals but is probably not the cause of the potentiated injury since the results showed that retinol treatment itself did not alter hepatic glutathione (3.34 +/- 0.43 vs 3.44 +/- 0.46 micromol/g for retinol vs vehicle, respectively). However, hepatic UDPGA stores were decreased in the retinol-treated group compared to untreated and corn oil controls (54.6 +/- 10.6 vs 200.6 +/- 17.6 nmol/g for retinol and untreated control, respectively, p < 0.001). This demonstrates that there is significantly less hepatic UDPGA available for conjugation following retinol administration. The results suggest that decreased hepatic UDPGA is likely the cause of retinol's potentiation of acetaminophen-induced hepatic injury.
Bray
B J
BJ
Department of Pharmacology, University of Otago Medical School, Dunedin, New Zealand.
Rosengren
R J
RJ
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D002384:Catalysis; D056486:Chemical and Drug Induced Liver Injury; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D004357:Drug Synergism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis; D014801:Vitamin A / Q000008:administration & dosage / Q000633:toxicity*
D014801:Vitamin A; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D005978:Glutathione