Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin.
Acetaminophen hepatotoxicity is characterized by glutathione depletion and the formation of the reactive electrophilic metabolite N-acetyl-p-benzoquinone imine. The induction of oxidative stress, expressed as lipid peroxidation, is controversial in acute acetaminophen intoxication. Isolated rat hepatocytes develop spontaneously or when incubated with buthionine sulfoximide, a progressive lipid peroxidation which may be inhibited by the antioxidant flavonoid silybin. When cells are incubated with acetaminophen, lipid peroxidation is not observed, this antilipoperoxidative effect being potentiated by silybin. It is proposed that when hepatocytes are incubated with a high concentration of acetaminophen, the drug may accumulate in the cells due to saturation and/or inhibition of detoxification pathways (as in the case of silybin). Under these conditions the development of hepatocyte oxidative stress may be inhibited due to the antioxidant behaviour of acetaminophen.
Unit of Biochemical Pharmacology, INTA, University of Chile, Santiago.
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Garrido
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Arancibia
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Campos
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Valenzuela
D000082:Acetaminophen / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D004357:Drug Synergism; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012838:Silymarin / Q000494:pharmacology*; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism*
D000975:Antioxidants; D012838:Silymarin; D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione