Studies in detoxication. 72. The metabolism of coumarin and of o-coumaric acid

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Abstract
Coumarin when fed to rabbits is hydroxylated to 3-, 7- and 8-hydroxycoumarins, which are excreted in conjugation. This also occurs in the ferret, guinea pig, mouse and rat, the first 3 of which also excrete 5-hydroxycoumarin. However, not more than 25% of the coumarin fed (dose 0-1 gAg) can be accounted for as conjugated glucuronic acid and ethereal sulfates excreted in the urine. The ethereal sul-fate and glucuronide of 3-hydroxycoumarin were isolated from the urine of rabbits fed on coumarin. 7-Hydroxycoumarin was also isolated after acid hydrolysis of the urine. 5- and 8-Hydroxycoumarins were not isolated but were detected in the hydrolyzed urine by paper chromatography. The hydroxylation of coumarin was carried out with Fenton''s reagent and an ascorbic acid-iron system. The results, which were not exactly the same as those found in vivo are discussed. o-Coumaric acid appears to be excreted unchanged to a large extent by rabbits. It is, however, directly conjugated to a small extent since its ether glucuronide, o-glucosidurone-trans-cinnamic acid, was isolated and its glycine conjugate, o-hydroxy-trans-cinnamoylglycine, was detected by paper chromatography in the urine. o-Coumaric acid is also cyclized in vivo, since small amounts of the glucuronide of 4-hydroxycoumarln were isolated from the urine and 7-hydroxycoumarin was detected chromato-graphically. Melilotic acid, the corresponding saturated acid (dihydro- coumaric acid), also yields 4- and 7-hydroxycoumarin in the rabbit. The mechanism of the cyclization of o-Coumaric acid is discussed and it is suggested that the coumarin derivatives formed arise from [beta]-oxidation products of o-Coumaric acid.