The Relationship between Chewcal Structure and Physiological Response Iv. Conjugation of Salicylic Acid with Glycine and Its Action on Uric Acid Excretion

The experimental studies on the fate of salicylic acid have yielded many conflicting results. In 1856, Bertagnini (1) reported 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 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 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 unsatisfactory 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