Spontaneous chemiluminescence production, lipid peroxidation, and covalent binding in rat hepatocytes exposed to acetaminophen.
Spontaneous chemiluminescence associated with the cell injury was observed in the isolated rat hepatocyte suspension during acetaminophen (APAP) metabolism, indicating the occurrence of oxidative stress. APAP apparently affected the hepatocytes in various manners. APAP, at low concentrations (1-2 mM), damaged the hepatocytes due to lipid peroxidation provoked during APAP metabolism, while at high concentrations (5-50 mM), APAP protected the hepatocytes due to a chemical antioxidant effect of the unmetabolized APAP that remained in the medium because of the saturation of APAP metabolism. The covalent binding of APAP to the hepatocytes increased with APAP concentration up to 50 mM without loss of cell viability. When an overdose of APAP was administered to rats, the APAP plasma concentration was around 1-3 mM, which corresponded to the concentration range where lipid peroxidation occurred in the isolated hepatocytes. Thus, it seems likely that lipid peroxidation contributes to the APAP-induced hepatotoxicity in the early stage of the toxic process.
Minamide
Y
Y
Department of Biopharmaceutics, Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0355, Japan.
Horie
T
T
Tomaru
A
A
Awazu
S
S
D000082:Acetaminophen / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D018384:Oxidative Stress / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D010655:Phenylenediamines; D011506:Proteins; D017392:Thiobarbituric Acid Reactive Substances; D000082:Acetaminophen; C004845:N,N'-diphenyl-4-phenylenediamine; D001219:Aspartate Aminotransferases; D005978:Glutathione