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Journal of Lipid Research, Vol. 46, 571-581, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Interfacial properties of most monofluorinated bile acids deviate markedly from the natural congeners

John M. Kauffman^*, Roberto Pellicciari and Martin C. Carey^1,*

^* Department of Medicine, Harvard Medical School, Harvard Digestive Diseases Center, and Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA
Dipartimento di Chimica é Tecnologia del Farmaco, Università di Perugia, Perugia, Italy

¹ To whom correspondence should be addressed. e-mail: mccarey{at}rics.bwh.harvard.edu

We characterized the air-water interfacial properties of four monofluorinated bile acids alone and in binary mixtures with a common lecithin, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), using an automated Langmuir-Pockels surface balance. We compared 7-fluoromurocholic acid (FMCA), 7-fluorohyodeoxycholic acid (FHDCA), 6-fluoroursodeoxycholic acid (FUDCA), and 6-fluorochenodeoxycholic acid (FCDCA) with their natural dihydroxy homologs, murocholic acid (MCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and chenodeoxycholic acid (CDCA). For further comparison, two trihydroxy bile acids, 3,6ß,7-trihydroxycholanoic acid [-muricholic acid (-MCA)] and 3,6,7ß-trihydroxycholanoic acid [-muricholic acid (-MCA)], with isologous OH polar functions to FMCA and FUDCA were also studied. Pressure-area isotherms of MCA, HDCA, UDCA, CDCA, and FMCA displayed sharp collapse points. In contrast, FHDCA, FUDCA, and FCDCA formed monolayers that were less stable than the trihydroxy bile acids, displaying second-order phase transitions in their isotherms. All natural and fluorinated bile acids condensed mixed monolayers with POPC, with maximal effects at molar bile acid concentrations between 30 and 50 mol%. Examination of molecular models revealed that the 7-F atom of the interfacially stable FMCA projects away from the 6ß-OH function, resulting in minimal steric interactions, whereas in FHDCA, FUDCA, and FCDCA, close vicinal interactions between OH and F polar functions result in progressive bulk solubility upon monolayer compression.

These results provide a framework for designing F-modified bile acids to mimic or diverge from the natural compounds in vivo.

Supplementary key words phosphatidylcholine • condensation • pressure-area isotherm • orientation • bulk solubility • farnesoid X receptor • spectroscopic imaging

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