Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25771127
DOI
10.1016/j.taap.2015.03.004
PII: S0041-008X(15)00086-1
Knihovny.cz E-resources
- Keywords
- Bile production, Bile salt export pump, Boldine, Farnesoid X receptor,
- MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 11 MeSH
- ATP-Binding Cassette Transporters deficiency genetics metabolism MeSH
- Administration, Oral MeSH
- Aporphines administration & dosage metabolism pharmacology MeSH
- Hep G2 Cells MeSH
- Madin Darby Canine Kidney Cells MeSH
- Cholagogues and Choleretics administration & dosage metabolism pharmacology MeSH
- Ethinyl Estradiol pharmacology MeSH
- Transcription, Genetic drug effects MeSH
- Glutathione metabolism MeSH
- Hepatobiliary Elimination MeSH
- Infusions, Intravenous MeSH
- Liver drug effects metabolism MeSH
- Kinetics MeSH
- Humans MeSH
- Osmosis MeSH
- Rats, Inbred Lew MeSH
- Rats, Transgenic MeSH
- Rats, Wistar MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins genetics metabolism MeSH
- Dogs MeSH
- Receptors, Cytoplasmic and Nuclear agonists genetics metabolism MeSH
- Signal Transduction drug effects MeSH
- Transfection MeSH
- Up-Regulation MeSH
- Bile metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP Binding Cassette Transporter, Subfamily B, Member 11 MeSH
- ATP-Binding Cassette Transporters MeSH
- Abcb11 protein, rat MeSH Browser
- ABCC2 protein, human MeSH Browser
- Abcc2 protein, rat MeSH Browser
- Aporphines MeSH
- boldine MeSH Browser
- Cholagogues and Choleretics MeSH
- Ethinyl Estradiol MeSH
- farnesoid X-activated receptor MeSH Browser
- Glutathione MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Receptors, Cytoplasmic and Nuclear MeSH
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.
References provided by Crossref.org
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