The role of calcium in the pathogenesis of gallstones: Ca++ electrode studies of model bile salt solutions and other biologic systems. With an hypothesis on structural requirements for Ca++ binding to proteins and bile acids.
Calcium is present in all pigment gallstones as a salt of one or more of the anions in bile which are most readily precipitable by calcium: (i) carbonate; (ii) bilirubinate; (iii) phosphate, and (iv) "palmitate". We term these "calcium-sensitive" anions. In addition, since cholesterol stones have been found to contain pigment stone centers, we postulate that calcium precipitation in bile is a critical event in the initiation of cholesterol gallstones, so that the latter should be considered a two-stage process: (i) precipitation of calcium salts to form a nidus, and (ii) precipitation of cholesterol from its supersaturated state on this nidus. Any measure which will reduce free [Ca++] in bile will reduce calcium lithogenicity; possible ways to reduce [Ca++] in bile are presented. One way is to increase Ca++ binding by normal biliary constituents; we have recently pointed out that bile salts are important buffers for Ca++ in bile by virtue of binding to both free and micellar bile salts. Here, we consider some of our Ca++ electrode studies of taurocholate, glycocholate, serum albumin, and simple molecules having terminal carboxyl (CO0-) or sulfonic (SO-3) ions. A brief history of the development of the Ca++ electrode is given, along with theoretical considerations of ionic activities and techniques of electrode measurements. From the various studies, a unifying hypothesis is proposed for the structural requirements of Ca++-binding to proteins (albumin) and free monomeric bile salts. For proteins, unconjugated bile salts and glycine-conjugated bile salts, it is proposed that Ca++ binding involves a reversible ion-exchange "site" in which a Ca++ ion is interposed between carboxyl (CO0-) and hydroxyl (OH) groups. For taurine-conjugated bile salts, this "site" is proposed to involve the interposition of a Ca++ ion between the side-chain SO-3 and cholanic ring OH groups. These studies are a first step toward modulation of Ca++ activity in bile.
D001646:Bile / Q000032:analysis*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism*; D002118:Calcium / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D002137:Calculi / Q000378:metabolism; D011232:Chemical Precipitation; D002769:Cholelithiasis / Q000209:etiology* / Q000378:metabolism; D004566:Electrodes; D006801:Humans; D008274:Magnesium / Q000032:analysis; D008823:Micelles; D009994:Osmolar Concentration; D010182:Pancreatic Diseases / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
D001647:Bile Acids and Salts; D001798:Blood Proteins; D008823:Micelles; D012709:Serum Albumin; D008274:Magnesium; D002118:Calcium