A B S T R A C T Ion-exchange calcium electrodes represent the first practical method for the direct measurement of ionized calcium [Ca"+] These studies were included as part of a symposium, January 1969 (1) and preliminary reports have appeared previously (2, 3).

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Calcium is present in all pigment gallstones as a sat 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 (COO-) or sulfonic (SO;) 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 (COO-) 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 SOT and cholanic ring OH groups. These studies are a first step toward modulation of Ca++ activity in bile.Gallstone disease is a major medical and surgical problem in many countries. In the United States, approximately 500,000 cholecystectomies are performed each year for cholelithiasis, with a direct cost of several billion dollars and indirect cost of several billions more due to time lost from work, to say nothing of the suffering and occasional mortality involved. The physical chemistry of bile is therefore of great interest to scientist and clinician This conference is not Only to Our old ideas, but to bring together investigators with different disciplines to focus on the multiplicity of factors involved in gallstone formation. We hypothesize that one icallY the free calcium ion concentration [Ca"] activThis work was supported by Research Grants AM 18887, AM 27104 and Am 32130, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, National Institutes of Health.The author wishes to apologize to the reader for not being able to include details of several unpublished studies which were presented at the Kroc Conference. This was necessary so as not to jeopardize ...

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