PHYSIOLOGICAL OCCURRENCE, BIOSYNTHESIS AND METABOLISM OF RETINOIC ACID - EVIDENCE FOR ROLES OF CELLULAR RETINOL-BINDING PROTEIN (CRBP) AND CELLULAR RETINOIC ACID-BINDING PROTEIN (CRABP) IN THE PATHWAY OF RETINOIC ACID HOMEOSTASIS
PHYSIOLOGICAL OCCURRENCE, BIOSYNTHESIS AND METABOLISM OF RETINOIC ACID - EVIDENCE FOR ROLES OF CELLULAR RETINOL-BINDING PROTEIN (CRBP) AND CELLULAR RETINOIC ACID-BINDING PROTEIN (CRABP) IN THE PATHWAY OF RETINOIC ACID HOMEOSTASIS
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DOI：
10.1016/0753-3322(91)90101-x
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发表时间：
1991-01-01
影响因子：
7.5
通讯作者：
BOERMAN, MHEM
中科院分区：
文献类型：
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作者：
NAPOLI, JL;POSCH, KP;BOERMAN, MHEM
本文将讨论最近的工作，视黄酸的生理发生，生物起源和代谢，并总结的数据，视黄酸是在原位合成的多种组织和细胞类型，通过酶或酶复合物，这是不同的醇脱氢酶。现在有相当多的证据表明，视黄酸是支持维生素A在体内的系统功能的视黄醇的活化代谢物。例如，许多体外研究表明视黄酸是最有效的天然类维生素A，其艾德-50范围为1 pM至10 nM，具体取决于测定系统。这低于维甲酸的组织浓度，其范围为约20-600 nM。维持在无血清培养基中的狗肾细胞系MDCK中由视黄醇合成视黄酸受到前列腺素类（PGE）和佛波酯（TPA）的抑制。在组织中，视黄酸合成的一个途径始于apo-CRBP，其通过微粒体的非胆酸盐依赖性视黄酯水解酶刺激视黄酯水解以形成holo-CRBP。全CRBP本身被NADP依赖性微粒体视黄醇脱氢酶用作底物以产生视黄醛，其被胞质NAD依赖性视黄醇脱氢酶转化为视黄酸。因此，细胞视黄醇结合蛋白（CRBP）显然在视黄酸合成中至少具有2种功能：载脂蛋白形式刺激视黄醇从视黄酯库中动员;全形式通过直接转移到脱氢酶来递送视黄醇。维甲酸通过睾丸微粒体转化为至少4种代谢产物的混合物，这些微粒体在反相HPLC上与4-羟基维甲酸紧密迁移，可能被误认为4-羟基或4-氧代-维甲酸。然而，更严格的分析表明，其中只有一种是4-羟基视黄酸，另一种是18-羟基视黄酸。另有两人身份不明。这些代谢物也在过量的细胞视黄酸结合蛋白（CRABP）存在下形成，其增加视黄酸的消除半衰期，但不能防止视黄酸催化剂，表明holo-CRABP可能是调节视黄酸稳态浓度的视黄酸催化剂的底物。因此，这两种类维生素A结合蛋白，CRBP和CRABP，可能各自具有直接的作用，作为底物在视黄酸的生物合成和代谢，分别。
This article will address recent work on the physiological occurrence, biogenesis and metabolism of retinoic acid and summarize the data that retinoic acid is synthesized in situ in multiple tissues and cell types via enzymes or enzyme complexes that are distinct from the alcohol dehydrogenases. There is now considerable evidence that retinoic acid is an activated metabolite of retinol that supports the systemic functions of vitamin A in vivo. Many studies in vitro, for example, have shown that retinoic acid is the most potent naturally-occurring retinoid with an ED-50 in the range of 1 pM to 10 nM, depending on the assay system. This is below the tissue concentrations of retinoic acid which range from approximately 20-600 nM. Retinoic acid synthesis from retinol in the dog kidney cell line MDCK maintained in serum-free medium is inhibited by the prostanoid, PGE, and the phorbol ester, TPA. In tissues, one pathway of retinoic acid synthesis begins with apo-CRBP stimulating retinyl ester hydrolysis by a microsomal, cholate-independent retinyl ester hydrolase to form holo-CRBP. The holo-CRBP itself is used as substrate by an NADP-dependent, microsomal retinol dehydrogenase to generate retinal, which is converted into retinoic acid by a cytosolic NAD-dependent retinal dehydrogenase. Therefore, cellular retinol-binding protein (CRBP) apparently has at least 2 functions in retinoic acid synthesis: the apo form stimulates retinol mobilization from retinyl ester stores: the holo form delivers the retinol via direct transfer to dehydrogenase(s). Retinoic acid is converted into a mixture of at least 4 metabolites by testes microsomes which migrate closely on reverse-phase HPLC with 4-hydroxyretinoic acid, and may be mistaken for either 4-hydroxy or 4-oxo-retinoic acid. More rigorous analysis, however, shows that only one of them is 4-hydroxyretinoic acid, and another is 18-hydroxyretinoic acid. Two others remain unidentified. These metabolites are also formed in the presence of excess cellular retinoic acid-binding protein (CRABP), which increases the elimination half-life of retinoic acid, but does not prevent retinoic acid catabolism, suggesting that holo-CRABP may be a substrate for retinoic acid catabolism that modulates the steady-state concentrations of retinoic acid. Thus, both retinoid binding proteins, CRBP and CRABP, may each have direct roles as substrate in the biosynthesis and metabolism of retinoic acid, respectively.