Biotransformation and biological activity of N-(4- hydroxyphenyl)retinamide derivatives in rodents

BN Swanson, DL Newton, PP Roller and MB Sporn

The metabolism and bioactivity of N-(4-hydroxyphenyl)-all-trans- retinamide (HPR) and of various O-alkyl and ester derivatives of HPR 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 (although not positively identified) is 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 degrees 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.

Volume 219, Issue 3, pp. 632-637, 12/01/1981
Copyright © 1981 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				A. Gupta, R. Nines, K. A. Rodrigo, R. A. Aziz, P. S. Carlton, D. L. Gray, V. E. Steele, M. A. Morse, and G. D. Stoner Effects of Dietary N-(4-Hydroxyphenyl)retinamide on N-Nitrosomethylbenzylamine Metabolism and Esophageal Tumorigenesis in the Fischer 344 Rat J Natl Cancer Inst, July 4, 2001; 93(13): 990 - 998. [Abstract] [Full Text] [PDF]