BIOTRANSFORMATION AND BIOLOGICAL-ACTIVITY OF N-(4-HYDROXYPHENYL)RETINAMIDE DERIVATIVES IN RODENTS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 219  (3) , 632-637
Abstract
The metabolism and bioactivity of N-(4-hydroxyphenyl)-all-trans-retinamide (HPR) and of various O-alkyl and ester derivatives of HPR, vitamin A analogs used clinically in various dermatoses and experiments in cancer chemoprevention, were investigated in rodents. The principal metabolite of HPR in tissues is N-(4-methoxyphenyl)-all-trans-retinamide. N-(4-methoxyphenyl)all-trans-retinamide is equipotent to HPR in reversing keratinization of retinoid-deficient hamster trachea in vitro. Another nonpolar metabolite of HPR is also present in tissue and thought to be a long-chain fatty acid ester of HPR. HPR is excreted into rat bile as numerous polar retinamides, including HPR-O-glucuronide. The rate of hydrolysis of HPR esters by rat serum and hepatic enzymes in vitro is inversely related to the length of the esterified acid side group. After a 30 min incubation at 37.degree. C in serum, percentage of hydrolysis for acetyloxy, propionyloxy, butyryloxy, pivaloyloxy and octanoyloxy esters of HPR is 41, 20, 7.5, 1.9 and 1.5, respectively. In contrast, hydrolysis by hepatic esterases is more rapid, particularly for the pivaloyloxy ester. Potency of the various HPR esters in the tracheal organ culture bioassay decreases as the length of the esterified side group increases; the acetyloxy ester is at least 5 times more potent than the octanoyloxy ester.