Retinoid Treatment for Oral Leukoplakia: Current Evidence and Future Development

Figure 1

The metabolism and mechanism of retinoids. Retinol travels in the bloodstream through binding to retinol-binding protein (RBP) and transthyretin (TTR). Through a transmembrane protein named STRA6, target cells can take up retinol into target tissues. Upon entering a target cell, retinol binds to cellular retinol-binding proteins (CRABPs), which are delivered to enzymes that transform it into retinoic acid. First, alcohol dehydrogenase or retinol dehydrogenase (ADH/RDH) reversibly oxidizes retinol to retinal tissue. Next, acetaldehyde dehydrogenase (ALDH) irreversibly converts retinal to retinoic acid (ATRA, 9-cis-RA, 13-cis-RA). Retinoic acid can then enter the nucleus to exert genomic effects. In the absence of ligands, RARs repress gene transcription by recruiting corepressors, and HDACs can remove acetyl groups from nucleosome histones, which can lead to chromatin condensation, prevent binding of other factors, and cause transcriptional silencing of the target gene. After ligand binding, RARs undergo structural changes, including the dissociation of corepressor complexes and the recruitment of coactivators. Histone acetyltransferases (HATs) can bring about epigenetic changes and chromatin depolymerization so that target genes can be normally transcribed. They can also activate kinase cascades to exhibit additional nontranscriptional effects or be degraded under the action of CYP26 enzymes.