title: Nifedipine modulation of biliary GSH and GSSG/ conjugate efflux in normal and regenerating rat liver.
abstract: Canalicular glutathione secretion provides the major driving force for bile acid-independent bile flow (BAIF), although the pathways involved are not established. The hypothesis that GSH efflux proceeds by a route functionally distinct from the high-affinity, low-capacity, mrp2-mediated pathway was tested by using perfused rat liver and three choleretic compounds that modify biliary secretion of GSH (the dihydropyridine nifedipine and organic anion probenecid) or GSSG [sodium nitroprusside (SNP)]. Whereas nifedipine (30 microM) stimulated GSH secretion and blocked SNP-stimulated GSSG efflux and choleresis, SNP (1 mM) was ineffective against nifedipine-stimulated GSH efflux or BAIF, suggesting that most GSSG exits through a GSH-inhibitable path independent of high-affinity GSSG/glutathione conjugate transport. Three observations support this proposal. SNP, but not nifedipine, significantly inhibited bromosulfophthalein (BSP, 1 microM) excretion. Probenecid (1 mM) blocked resting or nifedipine-stimulated GSH secretion but only weakly inhibited BSP excretion. Glutathione, but not BSP, efflux capacity was reduced following partial hepatectomy. We suggest GSH efflux is mediated by a high-capacity organic anion pathway capable of GSSG transport when its high-affinity route is saturated.
authors.affiliation: Gastrointestinal Diseases Research Unit and Department of Physiology, Queen's University, Kingston, Ontario K7L 5G2, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.forename: C E
authors.initials: CE
authors.lastname: Hill
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D001646:Bile / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism*; D007202:Indicators and Reagents / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D014528:Uricosuric Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D027321:Anion Transport Proteins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D007202:Indicators and Reagents; D014528:Uricosuric Agents; D014665:Vasodilator Agents; D013448:Sulfobromophthalein; D009599:Nitroprusside; D009569:Nitric Oxide; D005978:Glutathione; D009543:Nifedipine; D011339:Probenecid; D019803:Glutathione Disulfide