Inhibition effect of new farnesol derivatives on all-trans-retinoic acid metabolism.
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.
Kim
S Y
SY
Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
Kim
C
C
Han
I S
IS
Lee
S C
SC
Kim
S H
SH
Lee
K S
KS
Choi
Y
Y
Byun
Y
Y
D000963:Antimetabolites / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005204:Farnesol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006801:Humans; D008299:Maleic Anhydrides / Q000737:chemistry; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D013387:Succinic Anhydrides / Q000737:chemistry; D014212:Tretinoin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D005231:Fatty Acids, Unsaturated; D008299:Maleic Anhydrides; D013387:Succinic Anhydrides; C439728:mal-farnesol; C439729:suc-farnesol; D005204:Farnesol; D014212:Tretinoin; C031801:succinic anhydride; C007702:farnesoic acid