Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics.
Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics.
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DOI：
10.2174/1568026611313120004
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发表时间：
2013
影响因子：
3.4
通讯作者：
Isoherranen N
中科院分区：
文献类型：
--
作者：
Nelson CH;Buttrick BR;Isoherranen N
视黄酸（RA）是维生素A的活性代谢物，是调节细胞周期和上皮细胞维持的重要内源信号分子。 RA异构体还用作治疗各种癌症和皮肤病的药物。然而，由于致畸性和主要由RA代谢的自诱导产生的治疗耐药性等副作用，RA异构体的治疗用途受到限制。为了提高类维生素A的治疗效果，RA代谢阻断剂（RAMBA）被开发出来。这些抑制剂通常以细胞色素 P450 (CYP) 酶为目标，因为 RA 清除主要由 P450 介导。自从最初鉴定出 RA 代谢抑制剂以来，CYP26 酶已被定性为负责 RA 清除的主要酶。这使得 CYP26 酶成为开发癌症和皮肤病新型疗法的有吸引力的靶标。 CYP26抑制剂开发的基本原理是，在CYP26抑制剂存在的情况下，内源性RA的浓度会增加，从而以细胞类型特异性的方式增强内源性RA的活性。与 RA 给药相比，这将减少副作用，并允许更有针对性的治疗。在临床试验中，RA 代谢抑制剂可有效治疗牛皮癣和其他皮肤病以及某些癌症。然而，尚未有任何CYP26抑制剂被批准用于临床。本综述总结了 RAMBA 的发展历史、各种结构系列的临床和临床前研究以及 CYP26 抑制剂结构活性关系的现有知识。
Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity, and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.