Inhibition effect of new farnesol derivatives on all-trans-retinoic acid metabolism

All-trans-retinoic acid (atRA) is a promising anticancer and antiwrinkle dr ug. However, its clinical application is limited because it is rapidly meta bolized by the induced cytochrome P450 (P450). In this study, farnesol deri vatives are proposed as new inhibitors to prevent, P450-mediated metabolism . The farnesol derivatives were suc-farnesol and mal-farnesol, which were s ynthesized by the chemical conjugation of farnesol with succinic anhydride and maleic anhydride, respectively. The inhibition effects of farnesol, far nesoic acid, and farnesol derivatives on the atRA metabolism were evaluated in microsome and in AMC-HN-6 cells. In the microsome experiment, suc-farne sol and mal-farnesol strongly inhibited atRA metabolism at 10(-4) mol/L con centration by as much as 61% and 77%, respectively. In the cell experiment, the inhibition effects of farnesol derivatives on the atRA metabolism show ed similar tendency as the results in the microsome experiment, even if the effect was somewhat decreased. Effects of farnesoic acid and farnesol, how ever, were not significant. This research suggests that carboxylic end grou ps, such as atRA and hydrophobicity, might be important factors causing the higher inhibition effect, and that derivatization of farnesol can be 1 met hod to develop new inhibitors of atRA metabolism. Copyright (C) 2001 by W.S . Saunders Company.