title: Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms.
abstract: Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine.
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic; Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kadova
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Zagorova
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic; Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.affiliation: Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Tomsik
authors.affiliation: Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Nachtigal
authors.affiliation: Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Kudlackova
authors.affiliation: Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
authors.affiliation: Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Dubecka
authors.affiliation: Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.affiliation: Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Laho
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic. Electronic address: micuda@lfhk.cuni.cz.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001060:Aporphines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D065669:Hepatobiliary Elimination; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009995:Osmosis; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001060:Aporphines; D002756:Cholagogues and Choleretics; D004997:Ethinyl Estradiol; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000715087:ABCC2 protein, human; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; C011686:boldine
keywords: Bile production; Bile salt export pump; Boldine; Farnesoid X receptor