Kim S Y, Kim C, Han I S, Lee S C, Kim S H, Lee K S, Choi Y, Byun Y
Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
Metabolism. 2001 Nov;50(11):1356-60. doi: 10.1053/meta.2001.27190.
All-trans-retinoic acid (atRA) is a promising anticancer and antiwrinkle drug. However, its clinical application is limited because it is rapidly metabolized by the induced cytochrome P450 (P450). In this study, farnesol derivatives are proposed as new inhibitors to prevent P450-mediated metabolism. The farnesol derivatives were suc-farnesol and mal-farnesol, which were synthesized by the chemical conjugation of farnesol with succinic anhydride and maleic anhydride, respectively. The inhibition effects of farnesol, farnesoic acid, and farnesol derivatives on the atRA metabolism were evaluated in microsome and in AMC-HN-6 cells. In the microsome experiment, suc-farnesol and mal-farnesol strongly inhibited atRA metabolism at 10(minus;4) mol/L concentration by as much as 61% and 77%, respectively. In the cell experiment, the inhibition effects of farnesol derivatives on the atRA metabolism showed similar tendency as the results in the microsome experiment, even if the effect was somewhat decreased. Effects of farnesoic acid and farnesol, however, were not significant. This research suggests that carboxylic end groups, such as atRA and hydrophobicity, might be important factors causing the higher inhibition effect, and that derivatization of farnesol can be 1 method to develop new inhibitors of atRA metabolism.
全反式维甲酸（atRA）是一种很有前景的抗癌和抗皱药物。然而，其临床应用受到限制，因为它会被诱导的细胞色素P450（P450）迅速代谢。在本研究中，法尼醇衍生物被提议作为预防P450介导代谢的新型抑制剂。法尼醇衍生物为琥珀酰 - 法尼醇和马来酰 - 法尼醇，它们分别通过法尼醇与琥珀酸酐和马来酸酐的化学偶联反应合成。在微粒体和AMC - HN - 6细胞中评估了法尼醇、法尼酸和法尼醇衍生物对atRA代谢的抑制作用。在微粒体实验中，琥珀酰 - 法尼醇和马来酰 - 法尼醇在10⁻⁴mol/L浓度时强烈抑制atRA代谢，分别高达61%和77%。在细胞实验中，法尼醇衍生物对atRA代谢的抑制作用与微粒体实验结果呈现相似趋势，即便效果有所降低。然而，法尼酸和法尼醇的作用并不显著。本研究表明，诸如atRA的羧基端基团和疏水性可能是导致更高抑制效果的重要因素，并且法尼醇的衍生化可能是开发atRA代谢新抑制剂的一种方法。
