The role of heme oxygenase and aryl hydrocarbon hydroxylase in the protection by cysteamine from acetaminophen hepatotoxicity.
Administration of cysteamine to rats depressed hepatic aryl hydrocarbon hydroxylase (AHH) activity, cytochrome P-450, and total heme at 24 hr. Total heme remained decreased at 48 hr when all other parameters returned to control values. A significant 5-fold increase in heme oxygenase activity occurred in rat liver 5 hr after treatment, when AHH activity and total heme were unchanged. Histological examination of liver biopsies from rats treated with cysteamine revealed normal hepatic architecture. The observed effects of cysteamine on hepatic drug-metabolizing enzymes in vivo were not due to cysteamine-induced hepatotoxicity. Our results indicate that cysteamine increases heme oxygenase activity in rat liver, with a subsequent decrease in total heme, AHH activity, and cytochrome P-450 content. The depression of P-450 by cysteamine is likely to be an important mechanism for its protection in acetaminophen overdose. The protection studies illustrate this mechanism. Centrilobular hepatic necrosis and elevation in transaminase activity following a toxic dose of acetaminophen were prevented by treatment with cysteamine. The hepatoprotective effect of cysteamine was evident when acetaminophen was administered 24 hr after cysteamine but did not occur when acetaminophen was administered 5 hr after cysteamine or simultaneously. All groups of rats receiving cysteamine showed decreased mortality compared to the group receiving acetaminophen alone.
Peterson
T C
TC
Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Peterson
M R
MR
Williams
C N
CN
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D003543:Cysteamine / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D008099:Liver / Q000187:drug effects*; D008297:Male; D006899:Mixed Function Oxygenases / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D000082:Acetaminophen; D003543:Cysteamine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D006419:Heme Oxygenase (Decyclizing)