title: Bile acid toxicity structure-activity relationships: correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A).
abstract: The molecular mechanisms and interactions underlying bile acid cytotoxicity are important to understand for intestinal and hepatic disease treatment and prevention and the design of bile acid-based therapeutics. Bile acid lipophilicity is believed to be an important cytotoxicity determinant but the relationship is not well characterized. In this study we prepared new azido and other lipophilic BAs and altogether assembled a panel of 37 BAs with good dispersion in lipophilicity as reflected in RPTLC RMw. The MTT cell viability assay was used to assess cytotoxicity over 24 h in the HET-1A cell line (oesophageal). RMw values inversely correlated with cell viability for the whole set (r2=0.6) but this became more significant when non-acid compounds were excluded (r2=0.82, n=29). The association in more homologous subgroups was stronger still (r2>0.96). None of the polar compounds were cytotoxic at 500 microM, however, not all lipophilic BAs were cytotoxic. Notably, apart from the UDCA primary amide, lipophilic neutral derivatives of UDCA were not cytotoxic. Finally, CDCA, DCA and LagoDCA were prominent outliers being more toxic than predicted by RMw. In a hepatic carcinoma line, lipophilicity did not correlate with toxicity except for the common naturally occurring bile acids and their conjugates. There were other significant differences in toxicity between the two cell lines that suggest a possible basis for selective cytotoxicity. The study shows: (i) azido substitution in BAs imparts lipophilicity and toxicity depending on orientation and ionizability; (ii) there is an inverse correlation between RMw and toxicity that has good predictive value in homologous sets; (iii) lipophilicity is a necessary but apparently not sufficient characteristic for BA cytocidal activity to which it appears to be indirectly related.
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Cell Signalling, Institute of Molecular Medicine, Trinity Centre for Health Science, St. James's Hospital, Dublin, Ireland. rsharma@tcd.ie
authors: Ruchika
authors: R
authors: Sharma
authors: Ferenc
authors: F
authors: Majer
authors: Vijaya Kumar
authors: VK
authors: Peta
authors: Jun
authors: J
authors: Wang
authors: Ray
authors: R
authors: Keaveney
authors: Dermot
authors: D
authors: Kelleher
authors: Aideen
authors: A
authors: Long
authors: John F
authors: JF
authors: Gilmer
mesh_terms: D001647:Bile Acids and Salts / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival; D056148:Chromatography, Reverse-Phase; D002855:Chromatography, Thin Layer; D004947:Esophagus / Q000166:cytology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013329:Structure-Activity Relationship
chemical_list: D001647:Bile Acids and Salts