Effect of fasting on metabolite-mediated hepatotoxicity in the rat.
Acetaminophen and bromobenzene are transformed in the liver into chemically reactive metabolites that may either bind to glutathione and be detoxified or bind to hepatic proteins and produce liver cell necrosis. Fasting for 42 hr (a) decreased hepatic glutathione concentration, (b) increased the amount of chemically reactive metabolite irreversibly bound to hepatic proteins after administration of 3H-acetaminophen or 14C-bromobenzene, and (c) increased the hepatotoxicity of acetaminophen or bromobenzene. In rats fasted for various lengths of time, there was an inverse relationship between the concentration of glutathione in the liver and the activity of serum glutamic pyruvic transaminases after administration of acetaminophen or bromobenzene. In vitro, there was an inverse relationship between the concentration of glutathione in the incubate and the amount of chemically reactive metabolite bound to microsomal proteins after incubation of 3H-acetaminophen or 14C-bromobenzene with hepatic microsomes. It is concluded that fasting may decrease the inactivation of chemically reactive metabolites by glutathione, increase their binding to hepatic proteins, and enhance the hepatotoxicity of drugs transformed into chemically reactive metabolites that are detoxified by binding to glutathione.
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001711:Biotransformation; D001969:Bromobenzenes / Q000378:metabolism / Q000633:toxicity*; D002250:Carbon Radioisotopes; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D005215:Fasting; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013997:Time Factors; D014316:Tritium
D001969:Bromobenzenes; D002250:Carbon Radioisotopes; D014316:Tritium; D000082:Acetaminophen; D003035:Cobalt; D003577:Cytochrome P-450 Enzyme System; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D005982:Glutathione Transferase; D000410:Alanine Transaminase; D005978:Glutathione