Abstract
Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RA metabolism blocking agents (i.e., liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study, we used RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA in healthy and diseased reconstructed human epidermis. We unexpectedly discovered that DX314, but not all-trans-RA or previous RA metabolism blocking agents, appears to protect epidermal barrier integrity. In addition, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, the results indicate that DX314 inhibits all-trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a promising candidate compound for further study and development in the context of keratinization disorders.
| Original language | English |
|---|---|
| Pages (from-to) | 72-83.e6 |
| Journal | Journal of Investigative Dermatology |
| Volume | 141 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Funding
We would like to thank Drs B. Bienfait and J.S. Blairvacq (Clinique St. Luc, Namur-Bouge, Belgium) for providing skin samples used in this study. We would also like to thank Joanna Kreitinger and Larissa Walker of DermaXon and the Northwestern University Skin Biology and Diseases Resource-based Center (P30AR075049) for their assistance with various laboratory tasks. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease of the National Institute of Health: R44AR069416 (PD) and P20GM103546 (PD, JGSV). The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Health. Conceptualization: PD, JGSV, YP, ASP; Data Curation: JGSV; Formal Analysis: JGSV; Funding Acquisition: PD, ASP, JGSV; Investigation: JGSV; VDG, BB, HL; Methodology: JGSV, YP, PD, ASP; Project Administration: PD, JGSV, ASP, YP; Resources: JGSV, YP, PD, ASP, VDG, BB, HL; Software: JGSV; Supervision: PD, ASP, YP; Validation: JGSV, YP, PD, FB; Visualization: JGSV; Writing - Original Draft Preparation: JGSV; Writing - Review and Editing: JGSV, ASP, YP, PD We would like to thank Drs B. Bienfait and J.S. Blairvacq (Clinique St. Luc, Namur-Bouge, Belgium) for providing skin samples used in this study. We would also like to thank Joanna Kreitinger and Larissa Walker of DermaXon and the Northwestern University Skin Biology and Diseases Resource-based Center (P30AR075049) for their assistance with various laboratory tasks. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease of the National Institute of Health: R44AR069416 (PD) and P20GM103546 (PD, JGSV). The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Health.
| Funders | Funder number |
|---|---|
| P20GM103546 | |
| R44AR069416, P30AR075049 | |
| Northwestern University |
