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The Relationship Between Chewcal Structure and Physiological Response

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The Relationship Between Chewcal Structure and Physiological Response THE RELATIONSHIP BETWEEN CHEWCAL STRUCTURE AND PHYSIOLOGICAL RESPONSE IV. CONJUGATION OF SALICYLIC ACID WITH GLYCINE AND ITS ACTION ON URIC ACID EXCRETION BY ARMAND J. QUICK (From the Department of Surgery of the Fifth Avenue Hospital, New York) (Received for publication, May 3, 1933) Downloaded from The experimental studies on the fate of salicylic acid have yielded many conflicting results. In 1856, Bertagnini (1) re- ported that after ingesting salicylic acid he succeeded in isolating a compound consisting of glycine and salicylic acid which he named salicyluric acid because of its analogy to hippuric acid. Later www.jbc.org investigators who also reported finding salicyluric acid are Nencki (2), Lesnik (3), Moss0 (4), Bass (5), Baldoni (6), and Stockman (7). Hanzlik (8), however, failed to find salicyluric acid even by guest, on April 1, 2013 though he carefully followed the various procedures of the previous investigators. He therefore seriously questioned the occurrence of salicyluric acid in the urine. Several years later Holmes (9) reported the isolation of the conjugated product from human urine. He furthermore criticized the Thoburn-Hanzlik method (lo), which consists essentially in steam-distilling salicylic acid from urine strongly acidified with phosphoric acid, as unsatis- factory for determining salicyluric acid. From his quantitative studies Holmes concluded that salicylic acid is excreted in the ratio of 40 per cent free to 60 per cent combined with glycine. Holmes’ work has in turn been adversely criticized by Johnson (11). Recently the writer (12) in studying the conjugation of substituted benzoic acids discovered the rule that the union of glycine with a carboxyl group attached to a benzene ring is markedly inhibited by substitution in the ortho position. Since salicylic acid is o-hydroxybenzoic acid, its conjugation with glycine should be inhibited. It was found, as was anticipated, that the excretion of salicyluric acid was exceedingly small. On continuing 475 476 Salicylic Acid the study of salicylic acid, a simple method for isolating salicyluric acid was developed, which is described in this paper. Further quantitative studies on the conjugation of salicylic acid and on its influence on the excretion of uric acid are also reported. EXPERIMENTAL Both the successful isolation of salicyluric acid and the quanti- tative determination of free and combined salicylic acid employed in this work are based on the fact that these compounds can be completely removed from urine with ether by means of a con- Downloaded from tinuous extractor. The form01 titration method previously described by the author (13) for hippuric acid yields equally satis- factory results for salicyluric acid, and the writer’s adaptation of the Day and Taggard bromination method (14, 15) for total sali- cylic acid is simple and accurate. These methods have the ad- vantage that they can be applied to small volumes of urine and www.jbc.org that they have a high degree of accuracy yet are simple and rapid enough to be suitable for the analysis of routine hourly specimens. In studying the conjugation of salicylic acid and its influence on by guest, on April 1, 2013 the excretion of uric acid, the drug was always given orally in the form of the sodium salt. A light breakfast consisting of coffee and a cruller or toast was eaten 1 hour before the test. During the experimental period the subject was kept on a low protein and low purine diet. With a fairly well maintained standard diet, a remarkable constancy not only in the conjugation of salicylic acid but also on its stimulation of uric acid excretion was observed. Even after an interval of 1 year, the response to a fixed dose of the drug showed no greater variation than could be accounted for by the experimental errors inherent in the methods of analysis. Uric acid in the urine was determined by the Benedict-Hitchcock method (16). Isolation of Salicyluric Acid-Since hippuric acid and related compounds, which are always present in the urine after a mixed diet, cannot be separated from salicyluric acid, it is necessary for the isolation of pure salicyluric acid to put the subject on a low protein and a fruit- and vegetable-free diet for 24 hours prior to the test. 2.3 gm. of sodium salicylate are given orally and the urine collected for 24 hours, or if more convenient, for a shorter period. During the experiment only milk, bread, and sugar are A. J. Quick 477 allowed. If these dietary precautions are observed, pure salicyl- uric acid having the correct melting point is readily obtained, whereas on a mixed diet, the product although white and crystalline will not melt correctly even after repeated recrystallizations from water. The urine is made acid to litmus and concentrated on the water bath to about 100 cc. After the removal of the sediment, the urine is made acid to Congo red, and extracted with ether in a continuous extractor until the urine no longer gives a purple color with ferric chloride. After removing the ether by distillation, the gummy or crystalline residue is leached twice with hot toluene and Downloaded from once with chloroform. The crude product is dissolved in a small volume of boiling water, treated with decolorizing charcoal, filtered, and allowed to crystallize. Usually one recrystallization is sufficient to yield a colorless product but an additional simple extraction or washing with chloroform to remove traces of free salicylic acid may be necessary to obtain a pure compound. A www.jbc.org yield of about 0.5 gm. was obtained. In one experiment, 0.61 gm. was isolated from a 24 hour specimen of urine which from analysis was known to contain 0.96 gm. of salicyluric acid. by guest, on April 1, 2013 The melting point was found to be 167”, corrected. The accuracy of the thermometer was tested by determining the melt- ing point of pure salicylic acid. The present finding agrees with the melting point of the synthetic salicyluric acid as recorded by both Hanzlik and Holmes. Sa.licyluric acid crystallizes in the form of needle crystals which tend to be grouped in rosettes. Microscopically, the crystals differ from those of salicylic acid in being more lanceolated, while those of the latter compound have square ends. Salicyluric acid is practically insoluble in chloroform and toluene. It is very soluble in hot water and in cold water it is about four times as soluble as hippuric acid. The dry compound easily becomes electrically charged, a property also noted by Bondi (17) for the synthetic product. The compound gives a purple color with ferric chloride, and after hydrolysis gives a positive ninhydrin reaction. Salicyluric acid, like p-hydroxyhippuric acid, unites with 2 atoms of bromine, and like the para isomer, it gives on titration with standard sodium hydroxide a higher titration than the expected based on the monobasic acid. This indicates that the hydrogen of the hydroxy group of salicyluric acid is more acidic, i.e. ionized, than it is in salicylic acid. Bertag- 478 Salicylic Acid nini stated that he suspected that salicyluric acid is dibasic and Bondi also noted this property in the synthetically prepared compound. This is another illustration of how a change in one substituted group attached to the benzene ring can affect a second group. Analysis-Titration with 0.1 N sodium hydroxide: sample, 0.1 gm.; found, 6.4 cc.; calculated (for monobasic acid), 5.15 cc. Bromination: sample, 0.1 gm.; found, 0.159 gm. bromine; calculated, 0.164 gm. Glycine: sample, 0.1 gm.; found, 0.0352 gm.; calculated, 0.0384 gm. Downloaded from Determination of Acetylsalicylic Acid-A simple procedure for determining acetylsalicylic acid has been developed on the basis that this compound will not combine with bromine, whereas free salicylic acid, which is liberated on hydrolysis, will take up 3 atoms of bromine. Therefore, by determining the amount of www.jbc.org bromine consumed before and after hydrolysis, one can calculate the quantity of acetylsalicylic acid. If salicyluric acid is present, a correction must be made since this compound takes up 2 atoms of by guest, on April 1, 2013 bromine, but is also hydrolyzed. For the determination of acetylsalicylic acid in urine, 10 cc. samples are extracted, after the urine has been acidified, with ether in a continuous extractor. One sample is analyzed by the bromination met)hod directly, care being taken to keep the solution cold and allowing only 15 minutes for the reaction. A second sample is hydrolyzed by refluxing with 5 per cent sodium hydroxide before applying the bromination method. From the difference in the two titrations, the amount of salicylic acid combined with acetic acid can be calculated. A small fraction of the acetylsalicylic acid will be hydrolyzed during the determination, but the amount is surprisingly small and can be adequately corrected by a blank obtained by making a deter- mination with pure acetylsalicylic acid. DISCUSSION The human organism can synthesize salicyluric acid but the amount excreted is very small and is not markedly influenced by exogenous glycine, as can be seen in Table I. In agreement with Holmes, a definite ratio of free salicylic acid to salicyluric acid seems to exist, but this ratio varies with the dose of sodium A. J. Quick salicylate administered since the amount of uncombined salicylic acid increases more with increasing doses of the drug than the output of salicyluric acid. The excretion of salicylic acid is not rapid, contrary to the statement found in some text-books of pharmacology. Whereas the excretion of hippuric acid following TABLE I Conjugation of Xalicylic Acid in Man After Varying Doses of Sodium Salicylate Subject &.; weight, 52 kilos.
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