Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids: A study in isolated hepatocyte couplets and TR- rats

Mills, C.O.; Milkiewicz, P.; Müller, M.; Roma, M.G.; Havinga, R.; Coleman, R.; Kuipers, F.; Jansen, P.L.; Elias, E.

Journal of Hepatology 31(4): 678-684


ISSN/ISBN: 0168-8278
PMID: 10551392
DOI: 10.1016/s0168-8278(99)80348-1
Accession: 010463305

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Background/Aims: Fluorescent bile acids have proved useful for characterizing bile salt transport mechanisms. The aim of this study was to further validate the use of lysyl-fluorescein conjugated bile acid analogues as surrogate bile acids. Methods: We analyzed biliary excretion kinetics of cholyl lysyl fluorescein (CLF), lithocholyl lysyl fluorescein (LLF) and sulfo-lithocholyl lysyl fluorescein (sLLF), both in the isolated rat hepatocyte couplet model and in TR- rats with a selective canalicular transport defect of non-bile acid organic anions. Results: CLF and LLF, which like their natural non-sulfated bile acid congeners are expected to be handled by the canalicular bile salt export pump, were transferred into the bile canaliculus much faster than sLLF, a putative substrate for the canalicular multi-specific organic anion transporter in both the in vivo and the in vitro models employed. The contention that different transport systems are involved in sulfated and non-sulfated lysylfluorescein conjugated bile acids biliary excretion was supported further by studies using TR- rats, in which the cumulative biliary excretion of sLLF was reduced to 6% as compared with that of normal Wistar rats, in good agreement with values for its naturally-occurring radio-labeled parent compound sulfoglycolithocholate. In contrast, CLF and LLF were reduced to 66% and 52%, similar values to these for their congeners, (14C) glycocholate and (14C) lithocholate. Conclusion: The close similarity in behavior of lysyl fluorescein conjugated bile acids to that of their naturally-occurring parent compounds in these different models gives support for both sulfated and nonsulfated lysyl fluorescein conjugated bile acids as substitute molecules for studies of bile acid transport.