Swanson B N, Newton D L, Roller P P, Sporn M B
J Pharmacol Exp Ther. 1981 Dec;219(3):632-7.
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.
在啮齿动物中研究了N-(4-羟基苯基)-全反式视黄酰胺（HPR）以及HPR的各种O-烷基和酯衍生物的代谢和生物活性。HPR在组织中的主要代谢产物是N-(4-甲氧基苯基)-全反式视黄酰胺。N-(4-甲氧基苯基)全反式视黄酰胺在体外逆转类维生素A缺乏仓鼠气管的角质化方面与HPR具有同等效力。HPR的另一种非极性代谢产物也存在于组织中（尽管尚未明确鉴定），被认为是HPR的长链脂肪酸酯。HPR以多种极性视黄酰胺的形式排泄到大鼠胆汁中，包括HPR-O-葡萄糖醛酸苷。大鼠血清和肝酶在体外对HPR酯的水解速率与酯化酸侧链的长度呈负相关。在血清中于37℃孵育30分钟后，HPR的乙酰氧基、丙酰氧基、丁酰氧基、新戊酰氧基和辛酰氧基酯的水解百分比分别为41%、20%、7.5%、1.9%和1.5%。相比之下，肝酯酶的水解更快，尤其是对新戊酰氧基酯。在气管器官培养生物测定中，各种HPR酯的效力随着酯化侧链长度的增加而降低；乙酰氧基酯的效力至少是辛酰氧基酯的5倍。
