Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Aug;5(8):875-86.
doi: 10.1517/17425250903032681.

The role of CYP26 enzymes in retinoic acid clearance

Jayne E Thatcher  1 , Nina Isoherranen
Affiliations
Review

The role of CYP26 enzymes in retinoic acid clearance

Jayne E Thatcher et al. Expert Opin Drug Metab Toxicol. 2009 Aug.

Abstract

Retinoic acid (RA) is a critical signaling molecule that regulates gene transcription and the cell cycle. Understanding of RA signaling has increased dramatically over the past decades, but the connection between whole body RA homeostasis and gene regulation in individual cells is still unclear. It has been proposed that cytochrome P450 family 26 (CYP26) enzymes have a role in determining the cellular exposure to RA by inactivating RA in cells that do not need RA. The CYP26 enzymes have been shown to metabolize RA efficiently and they are also inducible by RA in selected systems. However, their expression patterns in different cell types and a mechanistic understanding of their function is still lacking. Based on preliminary kinetic data and protein expression levels, one may predict that if CYP26A1 is expressed in the liver at even very low levels, it will be the major RA hydroxylase in this tissue. As such, it is an attractive pharmacological target for drug development when one aims to increase circulating or cellular RA concentrations. To further the understanding of how CYP26 enzymes contribute to the regulation of RA homeostasis, structural information of the CYP26s, commercially available recombinant enzymes and good specific and sensitive antibodies are needed.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structure of all-trans retinoic acid with carbon positions labeled.
Figure 2
Figure 2
Analysis of CYP26 sequences in human, mouse and zebrafish. Comparison of amino acid sequence identity (percent identity) across species for CYP26A1, CYP26B1, and CYP26C1 (A) and across CYP26 subfamilies for human, mouse, and zebrafish (B). Numbers in brackets indicate the reference for gene alignment and % identity. [*] indicates alignments done for this manuscript using ClustalW. Panel (C) shows a phylogenetic three of human, mouse and zebrafish CYP26A1, CYP26B1, and CYP26C1. The CYP26A1 (Hs CAH72804.1, Dr NP_571221.2 and Mm NP_031837.2), CYP26B1 (Hs NP_063938.1, Dr AAQ82596.1, Mm AAH59246.1) and CYP26C1 (Hs NP_899230.2, Dr AAI29132.1, Mm AAI51107.1) genes were aligned using Vector NTI (Invitrogen) and phylogenetic tree was constructed based on the multiple alignment. Neither rigorous calculation of evolutionary distances nor phylogenetic relationship can be inferred with confidence from this tree.
Figure 3
Figure 3
Prediction of the relative contribution of CYP26A1, CYP2C8, CYP2C9, and CYP3A4 to liver clearance of at-RA using published Clint values and published expression levels of CYP2C8, CYP2C9 and CYP3A4. CYP26A1 concentration was set at 5 pmoles/mg liver (A) or 0 pmoles/mg liver (B–D) and 24 pmoles CYP2C8, 111 pmoles CYP3A4, and 73 pmoles of CYP2C9 per mg of liver was assumed in all predictions [78]. Intrinsic clearance values for RA metabolism by CYP3A4, CYP2C8 and CYP2C9 were obtained from [71] (A–B), [70] (C), and [72] (D). The different relative % contributions of CYP2C8, CYP3A4 and CYP2C9 are due to variable enzyme kinetic data for these proteins between publications.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tzimas G, Nau H. The role of metabolism and toxicokinetics in retinoid teratogenesis. Curr Pharm Des. 2001;7:803–31. - PubMed
    1. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. J Neurobiol. 2006;66:606–30. - PubMed
    1. Kane MA, Folias AE, Wang C, et al. Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry. Anal Chem. 2008;80:1702–8. - PMC - PubMed
    1. Tang GW, Russell RM. 13-cis-retinoic acid is an endogenous compound in human serum. J Lipid Res. 1990;31:175–82. - PubMed
    1. Tzimas G, Collins MD, Burgin H, et al. Embryotoxic doses of vitamin A to rabbits result in low plasma but high embryonic concentrations of all-trans-retinoic acid: risk of vitamin A exposure in humans. J Nutr. 1996;126:2159–71. - PubMed

Publication types