Investigation of adrenergic and prostaglandin influences in the endotoxin alteration of hepatic heme oxygenase, microsomal mixed-function oxidase, and glucocorticoid-induced tryptophan oxygenase activities.
The possible role for adrenergic influences or prostaglandins in the effects of endotoxin to inhibit the glucocorticoid induction of hepatic tryptophan oxygenase (TO) activity, to decrease the hepatic microsomal cytochrome P--450-dependent drug-metabolizing activity, and to induce heme oxygenase activity was examined. Administration of the alpha-adrenergic locking agents phenoxybenzamine or phentolamine attenuated the inhibitory effect of the bacterial lipopolysaccharide on the induction of TO activity by dexamethasone. Injection of a beta-adrenergic blocker, propranolol, or of indomethacin, an inhibitor of prostaglandin biosynthesis, accentuated the effect of endotoxin to inhibit TO induction. Neither phenoxybenzamine, propranolol, nor indomethacin altered the effect of endotoxin to decrease aniline hydroxylase activity, ethylmorphine N-demethylase activity, or the levels of cytochrome P--450. Also, dexamethasone administration did not significantly protect against the effects of endotoxin on the hepatic microsomal drug metabolizing enzyme system, and none of the pharmacological agents diminished the effects of endotoxin to induce hepatic heme oxygenase activity. Endotoxin administration was also shown to diminish, but not prevent, the induction of cytochrome P--450 and ethylmorphine N-demethylase activity produced by phenobarbital. The results indicate that alpha-adrenergic mechanisms are involved in the endotoxic inhibition of the glucocorticoid induction of TO activity and suggest that neither adrenergic influences nor prostaglandins play a significant role in the effect of endotoxin to decrease hepatic mixed-function oxidase activity.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014366:Tryptophan Oxygenase / Q000096:biosynthesis
D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D004731:Endotoxins; D005938:Glucocorticoids; D011453:Prostaglandins; D006899:Mixed Function Oxygenases; D014366:Tryptophan Oxygenase; D006419:Heme Oxygenase (Decyclizing)