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

Leuenberger, Michele; Häusler, 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), pp. 346-357. American Society for Pharmacology and Experimental Therapeutics 10.1124/jpet.120.000449

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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. Significance Statement Synthetic modification of common bile acids by attachment of small organic fluorescent dyes to the bile acid side chain resulted in bright, fluorescent probes that interact with hepatic and intestinal organic anion (OATP1B1, OATP1B3, OATP2B1), bile salt uptake (NTCP, ASBT) and bile salt efflux (BSEP, MRP2) transporters. Whilst the fluorescent bile salt derivatives are taken up into cells via the OATPs, the efflux transporters do not transport all but one of them.

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