Acetaminophen hepatotoxicity: influence of phenobarbital and beta-naphthoflavone treatment in obese and lean Zucker rats.
The effect of phenobarbital (PB) and beta-naphthoflavone (beta-NF) on acetaminophen (APAP)-induced hepatotoxicity was evaluated in obese and lean Zucker rats. In addition, the consequences of APAP overdose on hepatic CYP2B1/2B2 enzyme activities following PB treatment were assessed. A single oral dose of APAP 3 g/kg (total body weight) was administered to both littermates 24 hr after the last dose of PB or beta-NF. Histologic evidence of hepatocellular necrosis and serum hepatic aminotransferase enzymes 48 hr after APAP administration was utilized to evaluate hepatic damage. Hepatic microsomal total cytochrome P450 concentrations, alkoxyresorufin O-dealkylase activities, and 16 beta-testosterone hydroxylase activities were determined to evaluate the effect of APAP overdose on cytochrome P450 enzyme-substrate activities in the presence and absence of PB treatment. APAP overdose produced lower hepatotoxicity in the obese Zucker rat compared to lean controls. A similar trend was observed in animals treated with PB prior to APAP administration. In contrast, beta-NF treatment produced potentiation of APAP toxicity and/or death of both obese and lean Zucker rats. Generally, APAP overdose produced reduction of hepatic cytochrome P450 enzyme-substrate activities. However, obese Zucker rats retained a higher percentage of their pre-APAP-treated enzyme activities which is consistent with the observation that obese Zucker rats are less affected by the hepatotoxic effects of APAP overdosage.
Tuntaterdtum
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S
Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0082.
Chaudhary
I P
IP
Cibull
M
M
Robertson
L W
LW
Blouin
R A
RA
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004789:Enzyme Activation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000502:physiology; D009765:Obesity / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D000082:Acetaminophen; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010634:Phenobarbital