Header

UZH-Logo

Maintenance Infos

Characterization of Novel Fluorescent Bile Salt Derivatives for Studying Human Bile Salt and Organic Anion Transporters


Leuenberger, Michele; Hausler, Stephanie; Höhn, Vera; Euler, Adriana; Stieger, Bruno; Lochner, Martin (2021). Characterization of Novel Fluorescent Bile Salt Derivatives for Studying Human Bile Salt and Organic Anion Transporters. Journal of Pharmacology and Experimental Therapeutics, 377(3):346-357.

Abstract

Bile salts such as cholate, glycocholate, taurocholate and glycochenodeoxycholate are taken up from the portal blood into hepatocytes via transporters such as the Na+-taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptides (OATPs). These bile salts are later secreted into bile across the canalicular membrane, which is facilitated by the bile salt export pump (BSEP). Apart from bile salt transport, some of these proteins (e.g. OATPs) are also key transporters for drug uptake into hepatocytes. In vivo studies of transporter function in patients by using tracer compounds has emerged as an important diagnostic tool to complement classic liver parameter measurements by determining dynamic liver function both for diagnosis and monitoring progression or improvement of liver diseases. Such approaches include use of radioactively labeled bile salts (e.g. for PET) and fluorescent bile salt derivatives or dyes (e.g. indocyanine green). To expand the list of liver function markers, we have synthesised fluorescent derivatives of cholic and chenodeoxycholic acid by conjugating small organic dyes to the bile acid side chain. These novel fluorescent probes were able to block substrate transport in a concentration-dependent manner of NTCP, OATP1B1, OATP1B3, OATP2B1, BSEP and intestinal apical sodium-dependent bile salt transporter (ASBT). Whereas the fluorescent bile acid derivatives themselves were transported across the membrane by OATP1B1, OATP1B3 and OATP2B1 they were not transport substrates for NTCP, ASBT, BSEP and multidrug resistance-related protein 2 (MRP2). Accordingly, these novel fluorescent bile acid probes can potentially be used as imaging agents to monitor the function of OATPs.

Abstract

Bile salts such as cholate, glycocholate, taurocholate and glycochenodeoxycholate are taken up from the portal blood into hepatocytes via transporters such as the Na+-taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptides (OATPs). These bile salts are later secreted into bile across the canalicular membrane, which is facilitated by the bile salt export pump (BSEP). Apart from bile salt transport, some of these proteins (e.g. OATPs) are also key transporters for drug uptake into hepatocytes. In vivo studies of transporter function in patients by using tracer compounds has emerged as an important diagnostic tool to complement classic liver parameter measurements by determining dynamic liver function both for diagnosis and monitoring progression or improvement of liver diseases. Such approaches include use of radioactively labeled bile salts (e.g. for PET) and fluorescent bile salt derivatives or dyes (e.g. indocyanine green). To expand the list of liver function markers, we have synthesised fluorescent derivatives of cholic and chenodeoxycholic acid by conjugating small organic dyes to the bile acid side chain. These novel fluorescent probes were able to block substrate transport in a concentration-dependent manner of NTCP, OATP1B1, OATP1B3, OATP2B1, BSEP and intestinal apical sodium-dependent bile salt transporter (ASBT). Whereas the fluorescent bile acid derivatives themselves were transported across the membrane by OATP1B1, OATP1B3 and OATP2B1 they were not transport substrates for NTCP, ASBT, BSEP and multidrug resistance-related protein 2 (MRP2). Accordingly, these novel fluorescent bile acid probes can potentially be used as imaging agents to monitor the function of OATPs.

Statistics

Citations

Dimensions.ai Metrics
5 citations in Web of Science®
5 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

1 download since deposited on 08 Apr 2021
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Molecular Medicine, Pharmacology
Language:English
Date:1 June 2021
Deposited On:08 Apr 2021 08:07
Last Modified:25 Jun 2024 01:38
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/jpet.120.000449
PubMed ID:33782042
Project Information:
  • : FunderSNSF
  • : Grant ID51NF40-160620
  • : Project TitleNCCR TransCure: From transport physiology to identification of therapeutic targets (phase II)