Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

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.

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

“…The CYP26 family of cytochrome P450 (CYP26A1, CYP26B1, and CYP26C1) has been identified as being responsible for the metabolism of at-RA and its metabolites (Ray et al, 1997;Taimi et al, 2004;Guengerich, 2006;Lee et al, 2007;Lutz et al, 2009;Thatcher and Isoherranen, 2009;Helvig et al, 2011;Ross and Zolfaghari, 2011;Nelson et al, 2013). To date, however, no known xenobiotic compounds have been identified as substrates of CYP26A1 or CYP26B1, the two most characterized CYP26 isoforms.…”

Interplay between estrogen and retinoid signaling in breast cancer – Current and future perspectives

“…Indeed, RA regulates the expression of proteins involved in its own metabolism, such as CYP26, this way limiting the availability of RA and its biological activity [33,34]. CYP26 inhibitors, by increasing the endogenous concentrations of RA, potentiate its antitumor actions.…”

Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

“…Within the cytochrome P450 superfamily of xenobiotic metabolizing enzymes, the CYP26 subfamily (CYP26A1, CYP26B1 and CYP26C1) are the primary enzymes involved in retinoic acid metabolism [14][15][16][17][18] . While hepatic CYP26 content is primarily a function of CYP26A1 expression, CYP26A1 and CYP26B1 mRNA are ubiquitously expressed, with sites of expression including the skin, lungs, testes and brain 15,[18][19][20][21][22][23][24] . Less information is available about the expression patterns and functional relevance of CYP26C1.…”

“…A significant amount of catalytic overlap is observed for CYP26A1 and CYP26B1 in regard to their metabolism of at-RA, though the sequence homology between the two isozymes is only 42% 19,21,25 . Perhaps owing to their homeostatic role in the regulation of retinoic acid concentrations and the subsequent pharmacological or toxicological outcomes, the pursuit of selective chemical inhibitors of CYP26A1 or CYP26B1 has received interest in both the inflammation and oncology therapeutic areas [26][27][28][29][30][31][32][33][34] .…”

“…Many of the compounds designed to inhibit CYP26 activity, also known as retinoic acid metabolism blocking agents (RAMBAs), share a similar pharmacophore, with an extended hydrophobic region that bridges a hydrophobic or aromatic ring system on one end of the molecule to a hydrogen bond accepting group on the opposite end 35,36 . In many cases, the aromatic group described above is an azole-containing ring system, designed to coordinate to the porphyrin iron of CYP26A1 or CYP26B1 and thus inhibit the enzyme 19,29,30,[37][38][39] . Liarazole currently represents the most studied example of a RAMBA in clinical use 30,40 .…”