Retinoids comprise a family of polyisoprenoid lipids including vitamin A (retinol) and its natural and synthetic derivatives. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis [1
-retinoic acid (all-trans
-RA), the most potent biologically active metabolite of vitamin A, can both prevent and rescue the main defects caused by vitamin A deficiency in adult animals. In addition, 11-cis
-retinaldehyde plays a key role in the visual function. Recent evidence suggests that all-trans
-retinaldehyde is a regulator of adipogenesis, independent of its conversion to RA [3
]. Retinoids are being used in the treatment and prevention of particular cancer types [4
RA exerts its pleiotropic effects through binding to RA receptors (RARs), which bind to DNA as heterodimers with retinoid X receptors (RXRs). Both receptor types are members of the nuclear hormone receptor superfamily. As RXR/RAR heterodimers, these receptors control the transcription of RA target genes through binding to RA-response elements. Although RARs bind both all-trans
-RA and 9-cis
-RA, and 9-cis
-RA binds to RXRs, it is unnecessary for RXRs to bind a retinoid ligand for RA signaling [5
]. Also, because 9-cis
-RA has not been consistently detected in mammalian cells, the consideration of 9-cis
-RA as a natural bioactive retinoid remains controversial.
Retinoid transfer from liver, which is the major organ for the storage and metabolism of retinoids, to target tissues occurs mainly in the form of retinol bound to a specific plasma protein, retinol-binding protein (RBP), which delivers retinol to the target cells. In the cell, retinol has two metabolic alternatives: storage and oxidative metabolism. One form of storage is through binding to cellular retinol binding proteins (CRBPI and II). CRBPI shows wide tissue expression, while CRBPII is expressed in the small intestine. They are members of a family of small (~15 kDa) proteins that bind hydrophobic ligands such as long-chain fatty acids and retinoids [6
]. Their Kd
for retinol is in the low nM range. Therefore most retinol in the cell is bound to CRBP. The protein also binds retinaldehyde but with a higher Kd
. Retinol is also stored in the form of retinyl esters. Free retinol and CRBP-bound retinol are substrates for esterification by lecithin:retinol acyltransferase (LRAT), while retinyl ester hydrolase reverts this process.
Of great importance is the oxidative pathway of retinol metabolism, which generates RA. The first step is the reversible oxidation of retinol to retinaldehyde, catalyzed by different forms of alcohol dehydrogenase (ADH) from the MDR superfamily, and a variety of retinol dehydrogenases (RDHs) from the SDR superfamily. Recently retinaldehyde reductase activity has been detected in members of the aldo-keto reductase (AKR) superfamily [7
]. Retinaldehyde is irreversibly oxidized to RA by various retinaldehyde dehydrogenases (RALDH1, 2 and 3; i.e. ALDH1A1, 1A2, and 1A3), demonstrated by gene knockout studies in mice to be essential for embryonic development [8
]. RA can bind to cellular RA binding protein (CRABP), migrate to the nucleus for receptor binding, or be transformed to oxidized and mostly inactive compounds by CYP26, a cytochrome P450 enzyme [10
This review summarizes the in vitro and in vivo evidence for the role of ADHs and RDHs in the first step of RA biosynthesis.