Hepatotoxicity of acetaminophen and N-acetyl-p-benzoquinone imine and enhancement by fructose.
1. Although oral administration of 400 mg/kg acetaminophen (APAP) or 1.8-3.4 g/kg sucrose had no effect on serum levels of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH), their co-administration resulted in 20-fold increases in ALT/SDH activities. APAP alone (1250 mg/kg, p.o.) caused the elevation hepatotoxicity parameters, but the levels were lower than observed with co-administration of APAP (400 mg/kg) and sucrose (2.6 or 3.4 g/kg). 2. Sucrose-associated increase in serum ALT/SDH activities was selective with APAP and not detected with carbon tetrachloride (160 mg/kg, i.p.), D-galactosamine (400 mg/kg, i.p.) or alpha-naphthyl isothiocyanate (100 mg/kg, p.o.). 3. To verify the synergistic mechanism of sucrose, a major reactive intermediate of APAP, N-acetyl-p-benzoquinone imine (NAPQI), was given via the portal vein to rat pretreated with sucrose. Clear elevation of ALT/SDH activities was detected in the co-treated group. These results, together with an allopurinol-inhibition experiment, suggest the involvement of high-dose sucrose at a step(s) occurring after the metabolic activation of APAP. 4. Co-administration of glucose or fructose as well as sucrose elevated APAP-induced hepatotoxicity parameters in rat. Fructose but not glucose elevated APAP- or NAPQI-induced LDH leakage in a primary hepatocyte system. The results suggest the primary role of fructose is on the sucrose enhancement of APAP toxicity in rat.
Hojo
M
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Hanioka
K
K
Miyata
M
M
Yamazoe
Y
Y
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D007097:Imines / Q000633:toxicity*; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008107:Liver Diseases / Q000201:enzymology; D008297:Male; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007097:Imines; D005632:Fructose; D000082:Acetaminophen; D013395:Sucrose; D000493:Allopurinol; D003577:Cytochrome P-450 Enzyme System; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D014969:Xanthine Oxidase; D000410:Alanine Transaminase; C028473:N-acetyl-4-benzoquinoneimine; D005947:Glucose