Taurolithocholate increases heme catabolism and alters the clearance of antipyrine in the rat.
Taurolithocholate has been implicated in human cholestatic syndromes. Its action is believed to be due to an alteration in liver plasma membrane composition. To investigate whether other membranes are similarly affected, we studied the effect of taurolithocholate on hepatic heme turnover by means of a new 14CO breath test. Between 2 and 7 h after taurolithocholate administration, 14CO production was significantly increased, suggesting increased heme catabolism. This was substantiated by the finding of a 47% reduction of microsomal cytochrome P450 content 3 h after taurolithocholate administration. There was a reciprocal increase of 50% in heme oxygenase activity, the key enzyme in heme catabolism. To probe the biological significance of these findings, we measured plasma disappearance of propranolol and antipyrine. Clearance of neither propranolol nor antipyrine was altered by acute taurolithocholate administration. Prolonged administration of taurolithocholate, by contrast, decreased metabolic clearance rate of antipyrine by 48%. This was accompanied by a 25% decrease in microsomal cytochrome P450 content. Our findings suggest that taurolithocholate affects composition and function of the smooth endoplasmic reticulum, and that its action is not limited to the liver plasma membrane.
D000818:Animals; D000983:Antipyrine / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D008095:Lithocholic Acid / Q000031:analogs & derivatives*; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013658:Taurolithocholic Acid / Q000494:pharmacology*
D006418:Heme; D013658:Taurolithocholic Acid; D008095:Lithocholic Acid; D003577:Cytochrome P-450 Enzyme System; D000983:Antipyrine