Title:Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics
Volume: 13
Issue: 12
Author(s): Cara H. Nelson, Brian R. Buttrick and Nina Isoherranen
Affiliation:
Keywords:
Retinoic acid, cytochrome P450, CYP26, azole, cancer, psoriasis, metabolism, inhibition, RAMBA.
Abstract: 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.
