Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats: role of pharmacokinetics and metabolism of acetaminophen.
Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP), as compared with normal ones. The present study was designed to test the hypothesis that alterations in the distribution of APAP and in the intrinsic susceptibility to toxicants are responsible for the alteration in hepatorenal toxicity of APAP in fructose-induced hypertriglyceridemic rats. Following APAP-administration (750 mg/kg, i.p.), fructose-pretreated rats (25% fructose in drinking water for 5 weeks) showed nephrotoxicity of APAP more promptly and more severely than normal ones. Renal APAP-concentrations at the early phase (15 and 30 min. after APAP-administration) were significantly greater in fructose-pretreated rats than those in normal ones. Plasma and hepatic APAP concentrations in fructose-pretreated rats were greater than those in normal ones only at the later phase (plasma; 6 hr, liver; 6 and 12 hr after APAP-administration). There were no significant differences in the APAP-induced depletion of hepatic and renal glutathione and in the basal hepatic and renal cytochrome P-450 contents between these rats. Fructose-pretreated rats were also more susceptible to p-aminophenol (PAP), a nephrotoxic metabolite of APAP, than normal rats. Therefore, enhanced susceptibility to APAP-nephrotoxicity in fructose-pretreated rats may be due, at least in part, to increased renal APAP concentration and increased intrinsic susceptibility to the metabolic nephrotoxicant.
Ishida
K
K
Safety Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd. Tokyo, Japan.
Sakazume
M
M
Watanabe
M
M
Hirai
N
N
Ikegami
H
H
Sakai
T
T
Doi
K
K
D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000008:administration & dosage; D005978:Glutathione / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007700:Kinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D005632:Fructose; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione