title: Inhibition of Na+/H+ exchange in the rat is associated with decreased ursodeoxycholate hypercholeresis, decreased secretion of unconjugated urodeoxycholate, and increased ursodeoxycholate glucuronidation.
abstract: In the perfused rat liver, ursodeoxycholate in high dose produces an HCO3- -rich hypercholeresis which we have shown previously to be inhibited by replacement of perfusate Na+ with Li+ or by addition of amiloride (or amiloride analogues). In the present studies, we have determined whether such inhibition is associated with altered ursodeoxycholate biotransformation. Under control conditions, ursodeoxycholate infusion produced a 3.7-fold increase in bile flow and a 9.2-fold increase in biliary HCO3- output. By thin-layer chromatography, ursodeoxycholate radioactivity in bile was present in unconjugated form (15%) or as glycine or taurine amidates. Glucuronide conjugates of ursodeoxycholate accounted for less than 1% of biliary bile acids. Li+/Na+ substitution decreased ursodeoxycholate-stimulated bile flow and HCO3- secretion by greater than 90%, but decreased recovery of ursodeoxycholate and metabolites by only 25%. Amiloride or amiloride analogues decreased ursodeoxycholate-stimulated choleresis and HCO3- output by 38%-76%, yet did not cause decreased recovery of ursodeoxycholate and metabolites. Inhibition of the hypercholeresis was associated with a decrease in unconjugated ursodeoxycholate to less than 2% of total biliary bile acids, a striking increase in ursodeoxycholate glucuronides, and a reciprocal decrease in glycine and taurine amidates. With Li+/Na+ substitution, the predominant metabolites were a mixture of the 24-ester and the 3-aketal (ethereal) glucuronide (29%), and amidation with glycine appeared to be selectively inhibited; with amiloride or its analogues, only the 3-ethereal glucuronide was formed (20%-60% of biliary bile acids), and both taurine and glycine amidation were inhibited. Thus, maneuvers that decrease Na+/H+ exchange inhibit ursodeoxycholate hypercholeresis and cause replacement of unconjugated ursodeoxycholate in bile by its glucuronide. The secretion of unconjugated ursodeoxycholate, a lipophilic bile acid, appears to be necessary for hypercholeresis induced by high-dose ursodeoxycholate infusion.
authors: Department of Medicine, University of California, San Francisco.
authors: J R
authors: JR
authors: Lake
authors: E L
authors: EL
authors: Renner
authors: B F
authors: BF
authors: Scharschmidt
authors: E J
authors: EJ
authors: Cragoe
authors: L R
authors: LR
authors: Hagey
authors: K J
authors: KJ
authors: Lambert
authors: D
authors: D
authors: Gurantz
authors: A F
authors: AF
authors: Hofmann
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001646:Bile / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D005965:Glucuronates / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000378:metabolism*
chemical_list: D005965:Glucuronates; D007473:Ion Channels; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D000584:Amiloride; D008094:Lithium; D012964:Sodium