Molecular Pharmacology Fast Forward. Published on February 23, 2018 as DOI: 10.1124/mol.117.111039
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MOL #111039
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Introduction
Vitamin A (retinol; ROL), through its active metabolite retinoic acid (RA), plays a critical role in
regulation of gene transcription, cell proliferation, differentiation and apoptosis (Noy, 2010; Tang and
Gudas, 2011). Retinol is believed to be devoid of biological activity, and is metabolized by alcohol and
aldehyde dehydrogenases to retinoic acid (RA) (Fig.1; Napoli, 2012; Kedishvili, 2016). The endogenous
vitamin A metabolites detected in human serum include all-trans- (atRA), 9-cis-, 13-cis- and 9,13-di-cis-
RA, 4-oxo-13-cis-RA and 4-oxo-atRA (Fig. 1 and 2; Arnold et al., 2012). Of these retinoids, atRA activates
retinoic acid receptors (RARs) and is believed to be the most important and biologically active endogenous
RA isomer (Allenby et al., 1994; Chambon, 1996; Stevison et al., 2015). However, 13-cis-RA, 9-cis-RA
and 4-oxo-atRA can also activate RARs (Idres et al., 2002; Topletz et al., 2014). Due to this
pharmacological activity and their favorable in vivo pharmacokinetics, 13-cis-RA and 9-cis-RA are used to
treat acne, high risk neuroblastoma (Veal et al., 2007) and chronic hand eczema (Schmitt-Hoffmann et al.,
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011). Similarly, both 13-cis-RA and 9-cis-RA are teratogenic demonstrating classic retinoid effects
Willhite et al., 1986; Kraft and Juchau, 1993). 9-cis-RA is also a ligand of retinoid X receptors (RXRs)
with significantly higher binding affinity than atRA and 13-cis-RA (Åström et al., 1990; Heyman et al.,
992; Allenby et al., 1993), but the in vivo significance of 9-cis-RA is unclear. 4-oxo-atRA exhibits higher
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affinity to RARα and similar affinity to RARβ as atRA, (Pijnappel et al., 1993; Idres et al., 2002; Topletz
et al., 2014) consistent with its teratogenicity (Herrmann, 1995), and ability to modulate positional
specification in early embryo (Pijnappel et al., 1993). However, the role of the different RA isomers and 4-
oxo-atRA in human physiology is unclear.
Biological effects of RA isomers and metabolites are dependent on the RAR binding affinity and the
cellular concentrations of the retinoids. Therefore, strict regulation of the physiological concentrations of
endogenous retinoids via tissue specific expression of retinoid synthesizing and metabolizing enzymes and
retinoid binding proteins (Fig.1) is critical. The two enzymes of the CYP26 family, CYP26A1 and
CYP26B1, have been identified as key enzymes responsible for clearing atRA and in controlling atRA
concentrations (Fig.1). CYP26A1 appears to be the liver atRA hydroxylase eliminating biologically active
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