Cytochrome P450s in the regulation of cellular retinoic acid metabolism

Abstract

The active metabolite of vitamin A, retinoic acid (RA), is a powerful regulator of gene transcription. RA is also a therapeutic drug. The oxidative metabolism of RA by certain members of the cytochrome P450 (CYP) superfamily helps to maintain tissue RA concentrations within appropriate bounds. The CYP26 family--CYP26A1, CYP26B1, and CYP26C1--is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns. The CYP26A1 gene is regulated by multiple RA response elements. CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development. Enzyme kinetic studies have demonstrated that several CYP proteins are capable of metabolizing at-RA; however, it is likely that CYP26A1 plays a major role in RA clearance. Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future.

Figure 1

Metabolism of vitamin A, showing production and metabolism of retinoic acid (RA) (boxed). CYP, cytochrome P450.

Figure 2

Schema of the metabolism of retinoic acid (RA) to 4-hydroxy and 4-oxo metabolites (phase 1 metabolism) followed by glucuronidation to form water-soluble metabolites (phase 2 metabolism). Carbon positions where RA metabolism occurs are numbered; * indicates positions that were labeled in metabolic studies in rats in vivo (18, 83). CYP, cytochrome P450; UDP, uridine 5'-diphospho.

Figure 3

Relative abundance of CYP26A1 mRNA in rat tissues and CYP26A1 promoter regulation in HepG2 hepatocytes. (A) CYP26A1 mRNA is much more abundant in the liver compared with lung, small intestine, and testis of rats and is down-regulated in vitamin A deficiency. Northern blot analysis from (114). (B) Diagram of the CYP26A1 promoter showing three RAREs and a half site (RARE4), R1, R2, R3, and R4. Distances from the transcription start site are marked. Promoter activity (relative luciferase activity) in HepG2 cells for the full-length (FL) wild-type promoter sequence and response elements (R), and for sequences mutated (M), at M1, M2, M3, or M4. Whereas RA increased activity ~20 fold for the FL promoter, mutation of any one of the RARE sites reduced luciferase activity by 80% to 90%, indicating that all of these RAREs are necessary for the RA-induced expression of CYP26A1. Data from (124). Abbreviations: CYP, cytochrome P450; RARE, retinoic acid response element; VAD, vitamin A deficient; VAS, vitamin A sufficient.