Dew S E, Wardlaw S A, Ong D E
Vanderbilt University School of Medicine, Department of Biochemistry, Nashville, Tennessee 37232.
Cancer Res. 1993 Jul 1;53(13):2965-9.
Fenretinide (HPR), 13-cis-retinoic acid, and all-trans-retinoic acid are vitamin A derivatives used in the treatment of cancer and severe acne. Patients taking these drugs often show side effects resembling the symptoms of hypovitaminosis A, namely, night blindness and decreased plasma retinol levels. A dietary vitamin A deficiency is not suspected in these patients; therefore, interference with normal vitamin A metabolism seems likely. The effect of these drugs on two enzymes involved in vitamin A metabolism was investigated. At micromolar concentrations, all three derivatives were found to inhibit intestinal lecithin-retinol acyltransferase (LRAT) and to a lesser extent liver LRAT and intestinal retinal reductase. Inhibition of intestinal LRAT by HPR and 13-cis-retinoic acid was enhanced by preincubation prior to assay, whereas inhibition of the other activities was not. The Ki for the inhibition of intestinal LRAT by HPR was determined to be 24.1 +/- 5.6 microM. The ability of these drugs to inhibit retinal reduction and retinol esterification in vitro suggests an ability to interfere with normal vitamin A metabolism in vivo, particularly during absorption. This may be most significant for HPR, which is known to accumulate in the liver and intestine after chronic dosing.
芬维A胺（HPR）、13-顺式维甲酸和全反式维甲酸都是用于治疗癌症和重度痤疮的维生素A衍生物。服用这些药物的患者常出现类似维生素A缺乏症的副作用，即夜盲和血浆视黄醇水平降低。这些患者不存在饮食性维生素A缺乏的情况；因此，干扰正常维生素A代谢的可能性较大。研究了这些药物对参与维生素A代谢的两种酶的作用。在微摩尔浓度下，发现所有三种衍生物均能抑制肠道卵磷脂-视黄醇酰基转移酶（LRAT），对肝脏LRAT和肠道视网膜还原酶的抑制作用较小。在测定前进行预孵育可增强HPR和13-顺式维甲酸对肠道LRAT的抑制作用，而对其他活性的抑制作用则无此现象。HPR对肠道LRAT抑制作用的Ki值测定为24.1±5.6微摩尔。这些药物在体外抑制视网膜还原和视黄醇酯化的能力表明它们在体内有干扰正常维生素A代谢的能力，尤其是在吸收过程中。这对HPR可能最为重要，已知长期给药后HPR会在肝脏和肠道中蓄积。
