Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Telbisz, Ágnes; Homolya, László

doi:10.1517/14728222.2016.1102889

Cited by 45 publications

(31 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The disposition of bile salts involves the concerted activity of various transporters, including BSEP, which resides in the apical membrane of the hepatocyte (25,26). Association of BSEP inhibition with drug-related liver injury is still a matter of discussion (27,28).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of the Drug Interaction Potential of Doravirine

Bleasby

Fillgrove

Houle

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ϳ20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (Յ20%) were reported at doravirine concentrations of Ն10 M but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drugmetabolizing enzymes and transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of the Drug Interaction Potential of Doravirine

Bleasby

Fillgrove

Houle

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…As indicated before, there is no evidence that the precipitation of BAs at low pH (46) could explain this depletion. Alternatively, BA secretion by the liver might be reduced in CP patients by a feedback control of the liver BA synthesis and transport (47). Measurements of the plasma levels of 7-hydroxy-4-cholesten-3-one and fibroblast growth factor 19 would have helped in distinguishing between cholehepatic shunting of BAs and intestinal BA malabsorption [elevated 7-hydroxy-4-cholesten-3-one, reduced fibroblast growth factor 19 (48)] as an explanation for the BA phenotype in CP patients.…”

Section: Bas In Cp Patientsmentioning

confidence: 99%

Postprandial bile acid levels in intestine and plasma reveal altered biliary circulation in chronic pancreatitis patients

Humbert

Rainteau

Tuvignon

et al. 2018

Journal of Lipid Research

View full text Add to dashboard Cite

Bile acid (BA) secretion and circulation in chronic pancreatitis (CP) patients with exocrine pancreatic insufficiency (EPI) were investigated by simultaneously measuring postprandial levels of individual BAs in duodenal contents and blood plasma using LC-MS/MS. CP patients and healthy volunteers (HVs) were intubated with gastric and duodenal tubes prior to the administration of a test meal and continuous aspiration of duodenal contents. Pancreatic lipase outputs in CP patients were very low (0.7 ± 0.2 mg) versus HVs (116.7 ± 68.1 mg; < 0.005), thus confirming the severity of EPI. Duodenal BA outputs were reduced in CP patients (1.00 ± 0.89 mmol; 0.47 ± 0.42 g) versus HVs (5.52 ± 4.53 mmol; 2.62 ± 2.14 g; < 0.15). Primary to secondary BA ratio was considerably higher in CP patients (38.09 ± 48.1) than HVs (4.15 ± 2.37; < 0.15), indicating an impaired transformation of BAs by gut microbiota. BA concentrations were found below the critical micellar concentration in CP patients, while a high BA concentration peak corresponding to gallbladder emptying was evidenced in HVs. Conversely, BA plasma concentration was increased in CP patients versus HVs suggesting a cholangiohepatic shunt of BA secretion. Alterations of BA circulation and levels may result from the main biliary duct stenosis observed in these CP patients and may aggravate the consequences of EPI on lipid malabsorption.

show abstract

“…The bile secretion is exclusively driven by ABC transporters residing in apical membrane. ABCB11 or bile salt export pump (BSEP) is responsible for the transport of bile acids to the canalicular lumen [2,3], whereas ABCB4 (MDR3) flips phosphatidylcholine (PC) to the outer leaflet of the membrane, resulting PC efflux into the bile [4]. The ABCG5/G8 heterodimer is proposed to be responsible for the canalicular transport of cholesterol [5,6].…”

Section: Introductionmentioning

confidence: 99%

The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

One of the most promising applications of human pluripotent stem cells is their utilization for human-based pharmacological models. Despite the fact that membrane transporters expressed in the liver play pivotal role in various hepatic functions, thus far only little attention was devoted to the membrane transporter composition of the stem cell-derived liver models. In the present work, we have differentiated HUES9, a human embryonic stem cell line, toward the hepatic lineage, and monitored the expression levels of numerous differentiation marker and liver transporter genes with special focus on ABC transporters. In addition, the effect of bile acid treatment and polarizing culturing conditions on hepatic maturation has been assessed. We found that most transporter genes crucial for hepatic functions are markedly induced during hepatic differentiation; however, as regards the transporter composition the end-stage cells still exhibited dual, hepatocyte and cholangiocyte character. Although the bile acid treatment and sandwich culturing only slightly influenced the gene expressions, the stimulated cell polarization resulted in formation of bile canaliculi and proper localization of transporters. Our results point to the importance of membrane transporters in human stem cell-derived hepatic models and demonstrate the relevance of cell polarization in generation of applicable cellular models with correctly localized transporters. On the basis of our observations we suggest that conventional criteria for the evaluation of the quality of stem cell-derived hepatocyte-like cells ought to be augmented with additional elements, such as polarized and functional expression of hepatic transporters.

show abstract

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Cited by 45 publications

References 110 publications

In Vitro Evaluation of the Drug Interaction Potential of Doravirine

In Vitro Evaluation of the Drug Interaction Potential of Doravirine

Postprandial bile acid levels in intestine and plasma reveal altered biliary circulation in chronic pancreatitis patients

The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells

Contact Info

Product

Resources

About