Retinoic acid 4-hydroxylation

McSorley LC, Daly AK. 2000. Identification of human cytochrome P450 isoforms that contribute to all-trans-retinoic acid 4-hydroxylation. Biochem. Pharmacol. 60 517-26... 

Some compounds normally in body are oxidized by P450 2C9, including linoleic acid (epoxidation) and vitamin A (all-tran.s-retinoic acid, 4-hydroxylation) , although the physiological significance is unknown. 

Martini, R. and M. Murray (1993). Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation. Arch. Biochem. Biophys. 303, 57-66. 

CYP26 consists of three enzymes each representing a separate subfamily (Table 1) probably are all involved in retinoic acid hydroxylation. CYP26A1 is an all trans retinoic acid hydroxylase which degrades retinoic acid, an important signalling molecule for vertebrate development. It acts through retinoic acid receptors. The other CYP26 isozymes are also retinoic acid hydroxylases. 

Boyer, P.M., A. Ndayibagira and P.A. Spear. Dose-dependant stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3, 4, 4 -tetrachlorobiphyenyl. Environ. Toxicol. Chem. 19 700-705, 2000. 

Doyon, C., R. Fortin and P. Spear. Retinoic acid hydroxylation and teratogenesis in lake sturgeon (.Acipenserfulvescens) from the St Lawrence River and Abitibi region, Quebec. Can. J. Fish. Aquat. Sci. 56 1428-1436, 1999. 

Chen H, Fantel AG, Juchau MR. 2000. Catalysis of the 4-hydroxylation of retinoic acids by CYP3A7 in human fetal hepatic tissues. Drug Metab Dispos 28 1051-1057. 

Formation of retinoyl CoA, followed by formation of an ester with the hydroxyl group of tyrosine, threonine or serine, or a thio-ester with the sutfhydryl group of cysteine (Figure 2.7). The source of retinoic acid for... 

The effect of inhibitors on the biosynthesis of rubixanthin (114) and other hydroxylated carotenoids was studiedin Staphylococcus aureus. Retinol was metabolized in rat livers to give an acidic product which was allegedly different from retinoic acid. 

Another forefront technique to improve the function of the stratum corneum and enhance barrier repair in dry skin is the use of epidermal differentiation. A number of hormone receptors for epidermal differentiation have been identified. This family of receptors includes retinoic acid receptors, the steroid receptors, the thyroid receptors, the Vitamin D receptors, the peroxisome proliferator-activated receptors, the farnesol-activated receptors, and the liver-activated receptors. It is reported that these transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Examples of ligands for the last three transcription factors are fatty acids for the peroxisome proliferator-activated receptor, famesol for the farnesol-activated receptor, and hydroxylated cholesterol derivatives for the liver-activated receptor. The stimulation of epidermal differentiation stimulated the synthesis of involucrin, filaggrin, and the enzymes of the ceramide synthesis pathway (74). 

Generally, vitamin A serves three classes of functions (1) support of the differentiation of epithelial cells, (2) support of the viability of the reproductive system (fetal growth and vitality of the testes), and (3) utilization in the visual cycle. Dietary retinoic acid can support only the first function. Animals raised on diets containing retinoic acid as the only source of vitamin lose their ability to see in dim light and become sterile. In males, sperm production ceases. In females, fetuses are resorbed. Retinoic acid cannot be stored in the liver, as it lacks the hydroxyl group needed for attachment of the fatty acid. Retinyl esters, retinol, and retinal are interconvertible. Retinal can be oxidized to form retinoic acid. All three functions of vitamin A can be supported by dietary retinyl esters, retinol, or retinal. Although these forms can be converted to retinoic acid, retinoic acid apparently cannot be reduced to form retinal. These relationships are summarized in Figure 9.44. 

Exact positions for hydroxyl glucuronides are given when known. Abbreviations LA, lithocholic acid atRA, all frams-retinoic acid. 

Treatment of 60 with retinoic acid in the presence of (CF3C0)20 afforded 61. Acetylation of la-hydroxyl group of 58, hydrolysis and protection of 3p-hydroxyl group as a TBS ether afforded 62, which was treated in a similar manner as described above furnished 63 (Scheme (7)). The biological activities will be reported elsewhere. 

Induction and inhibition of P450 2C8 are not particular issues at this point. Although P450 2C8 may play a prominent role in the hepatic and renal oxidation of arachidonic acid and retinoic acid, no disease etiology has been implicated at this point. The most serious issue is probably any impact on the disposition of the cancer chemotherapeutic agent paclitaxel. Polymorphisms may have some effect on in vivo 6oi-hydroxylation - although any influence may be modulated in part by the contribution of P450 3A4 to other reactions . ... 

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