A novel mechanism for the enhancement of acetaminophen hepatotoxicity by phenobarbital.
Pretreatment of mice with multiple doses of phenobarbital (PB) potentiates N-acetyl-para-aminophenol (APAP) hepatotoxicity through induction of cytochrome P-450, thus increasing the formation of APAP-reactive metabolites. The objective of this report is to investigate the effect of a single oral dose of PB on APAP hepatotoxicity in mice. PB was administered (150 mg/kg) 1 hr before oral administration of APAP (400 mg/kg). Blood, liver and urine were collected from mice at 2, 4, 8, 12 and 24 hr after APAP treatment. Mortality rate and incidence of gross hepatic lesions were significantly higher in mice pretreated with PB than in mice treated with APAP alone. At 8, 12 and 24 hr post-APAP treatment, serum glutamic oxalacetic transaminase activity was significantly higher in mice receiving the combination treatment. Hepatic glutathione levels were significantly lower at 1 and 2 hr in mice pretreated with PB. Urinary excretion of APAP mercapturate, APAP sulfate and free APAP increased, whereas APAP glucuronide decreased, in mice pretreated with PB compared with mice treated with APAP alone. Covalent binding of [3H]APAP to hepatic microsomes was markedly increased after PB pretreatment. PB pretreatment was found to deplete uridine diphosphate glucuronic acid in livers of mice at 1 and 2 hr post-APAP treatment. These results indicate that the biochemical mechanism by which a single dose of PB enhances APAP hepatotoxicity does not involve cytochrome P-450 induction; interference with APAP glucuronidation may occur.
D000082:Acetaminophen / Q000633:toxicity*; D001711:Biotransformation / Q000187:drug effects; D002451:Cell Compartmentation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D005965:Glucuronates / Q000378:metabolism / Q000652:urine; D020723:Glucuronic Acid; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*
D005965:Glucuronates; D000082:Acetaminophen; D020723:Glucuronic Acid; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D010634:Phenobarbital