The metabolism of dehydroacetic acid (DHA)

Abstract

Dehydroacetic acid (DHA) labeled with C 14 in four carbon atoms has been synthesized. DHA administered orally to rabbits at a dose level of 250 mg/kg did not increase the urinary excretion of glucuronides or ethereal sulfates. Small oral doses (20–70 mg/kg) of C 14-DHA were not rapidly excreted. In 3–7 days rabbits excreted 70–80% of the dose in the urine, 7–10% in respiratory CO 2, and 2–3% in the feces; 8–17% remained in the tissues. In 4–5 days, rats excreted 20–40% in the urine, 10–25% in respiratory CO 2, and 10–20% in the feces; 5–26% remained in the tissues. In both rats and rabbits the highest radioactivity was found in the blood. Electrophoresis of human serum incubated with C 14-DHA showed that DHA is mainly associated with serum albumin and to a lesser extent with serum globulins. Three metabolites of DHA have been isolated from rabbit urine: triacetic acid lactone (TAL); a hydroxy-DHA, probably 3-glycoloyl-6-methyl-2,3-dihydropyran-2,4-dione; and metabolite X, which is probably the salt of triacetic acid lactone 3-carboxylic acid. A further metabolite, compound Y, which is not a pyrone but probably a degradation product of DHA, was detected. DHA and hydroxy-DHA react with ammonium salts to form the corresponding 1′-imino derivative, imino-DHA and imino-hydroxy-DHA. After administration of DHA to rats and rabbits, the DHA and hydroxy-DHA occur in the urine partly free and partly as the imino derivatives. The urines of rabbits receiving small oral doses of C 14-DHA contain an average of DHA (total) 5% of the dose, hydroxy-DHA (total) 20%, TAL 10%, urea 0.3%; metabolites X and Y were estimated to account for 20 and 15%, respectively. Similarly, rat urines contain DHA (total) 5%, hydroxy-DHA (total) 8%, TAL 1%, and urea 0.3%. At higher dose levels the percentages of dose excreted as DHA and hydroxy-DHA are markedly increased, and the percentages as metabolites X and Y markedly decreased. 2,6-Dimethyl-4-pyrone and its 3-carboxylic acid, deoxydehydroacetic acid; orcinol; malonic, succinic, oxalic, and acetic acids; and acetone were shown not to be urinary metabolites of DHA. DHA and hydroxy-DHA, but not TAL, were found in the feces and gut contents of rats after subcutaneous injection of DHA, suggesting that these two compounds are excreted in the bile. The pattern of excretion of metabolites after injection of DHA did not differ significantly from that following oral administration. C 14-DHA was metabolized by rat liver, but not kidney, to hydroxy-DHA, TAL, and CO 2. A pathway for the metabolism of DHA via hydroxy-DHA, compound X, TAL, and triacetic acid to acetoacetic acid and CO 2 is suggested. Because of the reactivity of the keto group of the acetyl side chain and the tendency of DHA and hydroxy-DHA to combine with the amino groups of proteins and other essential compounds, the administration of DHA might have serious deleterious effects. The ultraviolet absorption spectra, color reactions, and chromatographic behavior of the metabolites of DHA and a number of other pyrones are given.