Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem

Open AccessPublished:December 15, 1984DOI:
      This paper is only available as a PDF. To read, Please Download here.
      The structure of the bile acid molecule is described and correlated with physiochemical properties of bile acids such as solubility, ionization, and micelle formation. Recent measurements of the critical micellar concentration (CMC) of a large number of bile acids indicate that the CMC is influenced by both side chain and nuclear structure. Bile acids with hydroxy substituents on both sides of the steroid nucleus are non-amphipathic and do not form micelles, and decreasing the length of the side chain causes an exponential increase in the CMC. Bile acid ionization, measured by titration in alcohol-water mixtures, is shown to be uninfluenced by nuclear substituents; the pKa of all unconjugated bile acids is about 5. Interactions of bile acid solutions with Ca2+ are discussed; recent work indicates that cholyl conjugates bind Ca2+ as monomers in solution. Model systems relevant to biological processes are classified, as are some of the physicochemical parameters of these systems. Biological processes involving bile acids are tabulated, and corresponding model systems are assigned to each. Some biological processes such as bile acid transport show marked species differences, suggesting that physicochemical parameters are insufficient to explain biological differences. It is recommended that the physical chemist study a variety of bile acids, that the biologist study a variety of species, and that both collaborate to attempt to factor out the extent to which physicochemical properties of bile acids can explain their biological properties.


        • Fieser L.F.
        • Fieser M.
        Steroids. Reinhold, New York1959: 945
        • Lettre H.
        Zur Stereochemie der Sterine und Gallensaeuren.
        Berichte. 1935; 68: 766-773
        • Bergstrom S.
        • Danielsson H.
        • Samuelsson B.
        Formation and metabolism of bile acids.
        in: Bloch K. Lipide Metabolism. John Wiley & Sons, Inc., London, England1960: 291-336
        • Doisy Jr., E.A.
        Metabolism of bile acids in animals.
        in: Taylor W. The Biliary System. F. A. Davis Company, Philadelphia, PA1965: 129-143
        • Brauer R.W.
        Mechanisms of bile secretion.
        J. Am. Med. Assoc. 1959; 169: 1462-1466
        • Sperber I.
        Secretion of organic anions in the formation of urine and bile.
        Pharmacol. Rev. 1959; 11: 109-134
        • Wheeler H.O.
        Inorganic ions in bile.
        in: Taylor W. The Biliary System. F. A. Davis Company, Philadelphia, PA1965: 481-493
        • Sobotka H.
        The Physiological Chemistry of the Bile. Williams & Wilkins Company, Baltimore, MD1937: 202
        • Fieser L.F.
        • Rajagopolan S.
        Oxidation of steroids. III. Selective oxidation and acylations in the bile acid series.
        J. Am. Chem. Soc. 1950; 72: 5530-5536
        • Iwasaki T.
        Ueber die Konstitution der Ursodesoxycholsaeure.
        Z. Physiol. Chem. 1936; 224: 181-193
        • Kanazawa T.
        • Shimazaki A.
        • Sato T.
        • Hoshino T.
        Studies on the synthesis of ursodeoxycholic acid.
        Nippon Kagaku Zasshi (Jpn. J. Chem.). 1955; 76 (summary in Chem. Abst. 51: 17965, 1957): 297-301
        • Bachrach W.H.
        • Hofmann A.F.
        Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis.
        Dig. Dis. Sci. 1982; 27 (and 833-856): 737-761
        • Bloch H.M.
        • Berg B.N.
        • Rittenberg D.
        The biological conversion of cholesterol to cholic acid.
        J. Biol. Chem. 1943; 149: 511-517
        • Ruzicka L.
        In the borderland between biorganic chemistry and biochemistry.
        Anna. Rev. Biochem. 1973; 42: 1-20
        • Bergstrom S.
        • Danielsson H.
        Formation and metabolism of bile acids.
        in: Code C.F. Handbook of Physiology, Section 6. V. American Physiological Society, Washington, DC1968: 2391-2407
        • Haslewood G.A.D.
        Recent developments in our knowledge of bile salts.
        Physiol. Rev. 1955; 35: 178-196
        • Pellicciari R.
        • Cecchetti S.
        • Natalini B.
        • Roda A.
        • Grigolo B.
        • Fini A.
        Bile acids with a cyclopropylcontaining side chain. 1. Preparation and properties of 3α, 7β-dihydroxy-22, 23-methylene-5β-cholane-24-oic acid.
        J. Med. Chem. 1984; 27: 746-749
        • Josephson B.
        The circulation of the bile acids in connection with their production, conjugation, and excretion.
        Physiol. Rev. 1941; 21: 463-486
        • Lack L.
        • Weiner I.M.
        Intestinal absorption of bile salts and some biological implications.
        Gastroenterology. 1963; 22: 1334-1338
        • Tappeiner A.J.F.H.
        Ueber die Aufsaugung der Gallensaeuren alkalien im Duenndarme.
        Wien. Akad. Sitzber. 1878; 77: 281-304
        • Hofmann A.F.
        • Molino G.
        • Milanese M.
        • Belforte G.
        Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.
        J. Clin. Invest. 1983; 71: 1003-1022
        • LaRusso N.F.
        • Hoffman N.E.
        • Korman M.G.
        • Hofmann A.F.
        • Cowen A.E.
        Determinants of fasting and postprandial serum bile acid levels in healthy man.
        Am. J. Dig. Dis. 1978; 23: 385-391
        • Roda A.
        Sensitive methods for serum bile acid analysis.
        in: Barbara L. Dowling R.H. Hofmann A.F. Roda E. Bile Acids in Gastroenterology. MTP Press, Limited, Lancaster, England1983: 57-68
        • Ferraris R.
        • Colombatti G.
        • Fiorentini M.T.
        • Carosso R.
        • Arossa W.
        • De La Pierre M.
        Diagnostic value of serum bile acids and routine liver function tests in hepatobiliary diseases. Dig.
        Dis. Sci. 1983; 28: 129-136
        • Festi D.
        • Labate A.M.M.
        • Roda A.
        • Bazzoli F.
        • Frabboni R.
        • Rucci P.
        • Taroni F.
        • Aldini R.
        • Roda E.
        • Barbara L.
        Diagnostic effectiveness of serum bile acids in liver diseases as evaluated by multivariate statistical methods.
        Hepatology. 1983; 3: 707-714
        • Bergstrom S.
        • Danielsson H.
        On the regulation of bile acid formation in the rat liver.
        Acta Physiol. Scand. 1958; 43: 1-7
        • Shefer S.
        • Hauser S.
        • Bekersky I.
        • Mosbach E.H.
        Feedback regulation of bile acid biosynthesis in the rat.
        J. Lipid Res. 1969; 10: 646-655
        • Mekhjian H.S.
        • Phillips S.F.
        • Hofmann A.F.
        Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man.
        J. Clin. Invest. 1971; 50: 1569-1577
        • Hofmann A.F.
        • Poley J.R.
        Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection. I. Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride.
        Gastroenterology. 1972; 62: 918934
        • Hofmann A.F.
        • Thistle J.L.
        • Klein P.D.
        • Szczepanik P.A.
        • Yu P.Y.S.
        Chenotherapy for gallstones. II. Induced changes in bile composition and gallstone response.
        J. Am. Med. Assoc. 1978; 239: 1138-1144
        • Iser J.H.
        • Dowling R.H.
        • Mok H.Y.I.
        • Bell G.D.
        Chenodeoxycholic acid treatment of gallstones.
        N. Engl. J. Med. 1975; 293: 378-383
        • Maton P.N.
        • Murphy G.M.
        • Dowling R.H.
        Ursodeoxycholic acid treatment of gallstones. Dose-response study and possible mechanism of action.
        Lancet. 1977; 2: 1297-1301
        • Thistle J.L.
        • LaRusso N.F.
        • Hofmann A.F.
        • Turcotte J.
        • Carlson G.L.
        • Ott B.J.
        Differing effects of ursodeoxycholic acid or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man: a dose-response study.
        Dig. Dis. Sci. 1982; 27: 161-168
        • Maton P.N.
        • Iser J.H.
        • Reuben A.
        • Saxton H.M.
        • Murphy G.M.
        • Dowling R.H.
        Outcome of chenodeoxycholic acid (CDCA) treatment in 125 patients with radiolucent gallstones.
        Medicine. 1982; 61: 86-97
        • Roda E.
        • Bazzoli F.
        • Labate A.M.M.
        • Mazzella G.
        • Roda A.
        • Sama C.
        • Festi D.
        • Aldini R.
        • Taroni F.
        • Barbara L.
        Ursodeoxycholic acid vs. chenodeoxycholic acid as cholesterol gallstone-dissolving agents: a comparative randomized study.
        Hepatology. 1982; 2: 804-810
        • Tennent D.M.
        • Siegel H.
        • Zanetti M.E.
        • Kuron G.W.
        • Ott W.H.
        • Wolf F.J.
        Plasma cholesterol lowering action of bile acid binding polymers in experimental animals.
        J. Lipid Res. 1960; 1: 469-473
        • Lipid Research Clinics Program
        The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidents of coronary heart disease to cholesterol lowering.
        J. Am. Med. Assoc. 1984; 251: 351-374
        • Neubauer E.
        Dehydrocholsaeure, ein wirksames ungiftiges Glied der Gallensaeurengruppe.
        Klin. Wochenschr. 1923; 2: 1065-1067
        • Holsti P.
        Bile acids as a cause of liver injury: cirrhogenic effect of chenodeoxycholic acid in rabbits.
        Acta Pathol. Microbiol. Scand. 1962; 54: 479
        • Palmer R.H.
        Bile acids, liver injury, and liver disease.
        Arch. Intern. Med. 1972; 130: 606-617
        • Swell L.
        • Trout Jr., E.C.
        • Hopper J.R.
        • Field Jr., H.
        • Treadwell C.R.
        Specific function of bile salts in cholesterol absorption.
        Proc. Soc. Exp. Biol. Med. 1958; 98: 174-176
        • Watt S.
        • Simmonds W.J.
        Effect of four taurine-conjugated bile acids on mucosal uptake and lymphatic absorption of cholesterol in the rat.
        J. Lipid Res. 1984; 25: 448-455
        • LaRusso N.F.
        • Hoffman N.E.
        • Hofmann A.F.
        • Northfield N.C.
        • Thistle J.L.
        Effect of primary bile acid ingestion on bile acid metabolism and biliary lipid secretion in gallstone patients.
        Gastroenterology. 1975; 69: 1301-1314
        • LaRusso N.F.
        • Szczepanik P.A.
        • Hofmann A.F.
        • Coffin S.B.
        Effect of deoxycholic acid ingestion on bile acid metabolism and biliary lipid secretion in normal subjects.
        Gastroenterology. 1977; 72: 132-140
        • McBain J.W.
        • Merrill Jr., R.C.
        • Vinograd J.R.
        The solubilization of water-insoluble dye in dilute solutions of aqueous detergents.
        J. Am. Chem. Soc. 1941; 63: 670-676
        • Ekwall P.
        Micelle formation in sodium cholate solutions.
        Acta Acad. Aboensis Math. Phys. 1951; 17: 3-10
        • Ekwall P.
        The solubilization of lipophilic substances by bile acid salts.
        in: Ruyssen R. Proceedings of the First International Conference on Biochemistry. Problems of Lipids. Brussels, 1953: 103-119
        • Hartley G.S.
        Aqueous solutions of paraffin-chain salts. A study in micelle formation.
        Actualites Scientifiques et Industrielles. Hermann & Cie, Paris1936
        • Hartley G.S.
        Solutions of soap-like substances.
        Prog. Chem. Fats Other Lipids. 1955; 3: 20-55
        • Mellander O.
        • Stenhagen E.
        The state of bile salt solutions. I. Introduction. II. Conductivity measurements on dilute solutions of sodium taurocholate at 25°C.
        Acta Physiol. Scand. 1942; 4: 349-361
        • Norman A.
        Preparation of conjugated bile acids using mixed carboxylic acid anhydrides.
        Arkiv. Kemi. 1955; 8: 331-342
        • Norman A.
        • Sjövall J.
        On the transformation and enterohepatic circulation of cholic acid in the rat.
        J. Biol. Chem. 1958; 233: 872-885
        • Norman A.
        The beginning solubilization of 20- methylcholanthrene in aqueous solutions of conjugated and unconjugated bile acid salts.
        Acta Chem. Scand. 1960; 14: 1295-1299
        • Norman A.
        The conductance of conjugated and unconjugated bile acid salts in aqueous solutions.
        Acta Chem. Scand. 1960; 14: 1300-1309
        • Small D.M.
        • Bourges M.C.
        • Dervichian D.G.
        The biophysics of lipidic associations. I. The ternary systems lecithin-bile salt-water.
        Biochim. Biophys. Acta. 1966; 125: 563-580
        • Iida T.
        • Chang F.C.
        Potential bile acid metabolites. 6. Stereoisomeric 3, 7-dihydroxy-5β-cholanic acids.
        J. Org. Chem. 1982; 47: 2966-2972
        • Iida T.
        • Chang F.C.
        Potential bile acid metabolites. 7. 3, 7, 12-Trihydroxy-5β-cholanic acids and related compounds.
        J. Org. Chem. 1982; 47: 2972-2978
        • Shaw R.
        • Elliott W.H.
        Bile acids. XXIX. Allo bile acids.
        in: Nair P.P. Kritchevsky D. The Bile Acids: Chemistry, Physiology, and Metabolism. I. Plenum, New York1971: 47-78
        • Tserng K-Y
        • Hachey D.L.
        • Klein P.D.
        An improved procedure for the synthesis of glycine and taurine conjugates of bile acids.
        J. Lipid Res. 1977; 18: 404407
        • Lack L.
        • Dorrity Jr., F.O.
        • Walker T.
        • Singletary G.D.
        Synthesis of conjugated bile acids by means of a peptide coupling reagent.
        J. Lipid Res. 1973; 14: 367-370
        • Carey M.C.
        • Igimi H.
        Physical-chemical basis for dissimilar intraluminal solubilities and intestinal absorption efficiencies of chenodeoxycholic and ursodeoxycholic acids.
        Bile Acids and Lipids. G. Paumgartner, 1981