Bile acid sulfates. I. Synthesis of lithocholic acid sulfates and their identification in human bile.

Sulfate esters of lithocholic, glycolithocholic, and taurolithocholic acids were synthesized using sulfur trioxide in pyridine; they were purified by crystallization from methanol or ethanol as the diammonium salts, and their chemical compositions, infared spectra, and chromatographic behavior were determined. Strong alkaline hydrolysis of these sulfates, as commonly performed during quantitative and qualitative analyses of conjugated bile salts, was found to result in a number of degradation products, presumably through disruption of the C-O bond of the hydroxyl group and conversion of the original steroid to isolithocholate and other (possibly olefinic) compounds. After oral administration of lithocholate-(14)C to three patients with cholelithiasis, radioactive metabolites having the chromatographic properties of sulfated lithocholates were isolated from bile and, confirming a preliminary report (1), were identified as sulfated glycolithocholate and taurolithocholate by their characteristic chromatographic mobilities during a series of specific hydrolytic procedures and by crystallizing them to constant specific activities with the synthetic sulfates. The fraction of endogenous lithocholate present in bile as the sulfate was calculated for two patients by isotope dilution and was shown to be 41% and 75% of the total. Sulfation can be expected to affect the physiological and pharmacological properties of lithocholates and may, therefore, influence the toxic properties of these compounds.