Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases

The Cytochrome P450 (CYP) family 26 enzymes contribute to retinoic acid (RA) metabolism and homeostasis in humans, mammals and other chordates. The three CYP26 family enzymes, CYP26A1, CYP26B1 and CYP26C1 have all been shown to metabolize all-trans-retinoic acid (atRA) it's 9-cisRA and 13-cisRA isomers and primary metabolites 4-OH-RA and 4-oxo-RA with high efficiency. While no crystal structures of CYP26 enzymes are available, the binding of various ligands has been extensively explored via homology modeling. All three CYP26 enzymes are inducible by treatment with atRA in various prenatal and postnatal tissues and cell types. However, current literature shows that in addition to regulation by atRA, CYP26 enzyme expression is also regulated by other endogenous processes and inflammatory cytokines. In humans and in animal models the expression patterns of CYP26 enzymes have been shown to be tissue and cell type specific, and the expression of the CYP26 enzymes is believed to regulate the formation of critical atRA concentration gradients in various tissue types. Yet, very little data exists on direct disease associations of altered CYP26 expression or activity. Nevertheless, data is emerging describing a variety of human genetic variations in the CYP26 enzymes that are associated with different pathologies. Interestingly, some of these genetic variants result in increased activity of the CYP26 enzymes potentially leading to complex gene-environment interactions due to variability in dietary intake of retinoids. This review highlights the current knowledge of structure-function of CYP26 enzymes and focuses on their role in human retinoid metabolism in different tissues. (C) 2019 Elsevier Inc. All rights reserved.