Retinyl-/?-glucuronide

Besides synthetic derivatives useful in therapy there exists a natural derivative of retinol (98), and retinoic acid(s) e. g., all-fraws-retinyl 8-glucuronide (99) [183] and all-fraws-retinoyl P-glucuronide (100) [184]. These vitamin A glycosides were first identified as billiary mefabo-lites of vitamin A, and they are now prepared also chemically for their favorable biological effects [185,186]. 

The conversion of frans-retinyl acetate into retinoic acid in hamster organ culture,262 and of cis- and trans-rzimoxc acid into the 5,6-epoxy- and 4-oxo-derivatives and their glucuronides has been demonstrated.263 264 Strains of Aspergillus niger metabolize ionones and related compounds to oxygenated derivatives, some of which may be useful intermediates for carotenoid synthesis. The asymmetric oxidation of p-ionone to (25, 6/ ,7/ )-2,7-epoxydihydro-a-ionone (218) has been demonstrated.265 (i )-4-Hydroxy-p-ionone (219 X = OH)... 

Barua, A. B., Olson, J. A. (1987). Chemical synthesis and growth- promoting activity of all-tranj -retinyl p-D-glucuronide, Biochem. J., 244 231. 

Eleven retinols (e.g., 4-oxoretinoic acid, 4-oxoretinol, retinoyl-] - and rrtinyl-/ -glucuronide, retinoic acid, 5,6-epoxyretinol, retinol) and retinyl acetate, linoleate. 

Figure 1 Some naturally occuring retinoids (a) all-fra/ii -retinol (b) all-frans-retinal (c) all-fran5 -retinoic acid (d) 13-cw-retinoic acid (e) all-frani-3,4-didehydroretinol (vitamin Aj alcohol) (f) 11-cw-retinal (g) all-franj-5,6-epoxyretinol (h) all-irani-anhydroret-inol (i) all-rran5 -4-oxoretinol (j) all-irans-retinoyl 5-glucuronide (k) all-frani-retinyl i-glucuronide (1) all-franj-retinyl palmitate.

In the plasma, vitamin A is transported from its major depots in the liver to tissues in several forms, primarily as a 1 1 molar complex of all-frans-retinol with RBP. Low concentrations of dll-trans- and 13-ds-retinoic acid, probably bound to albumin, and retinyl and retinoyl p-glucuronides, are also present. Holo-RBP also interacts strongly with transthyretin in the plasma. All of these forms of vitamin A can be taken up by various tissue cells. Several tissues besides the parenchymal cells of the liver can also synthesize RBP, as evidenced by the presence of mRNA for RBP within such cells. Thus, the extensive recycling of retinol between the liver and peripheral tissue cells may well occur as complexes with RBP. Another possibility is that retinyl ester, which is synthesized in essentially all cells of the body, might be carried back to the liver in lipoproteins. 

The current leading hypothesis is that nuclear RAR and RXR play a direct role in this process. The retinoid receptors can be activated by physicochemical binding of free retinoic acid to RAR and RXR. Alternatively, covalent forms, such as retinoyl derivatives of RAR and RXR, might also exist. Interestingly, retinyl and retinoyl p-glucuronide stimulate the differentiations of HL-60 cells well without evident conversion to retinol and retinoic acid, respectively. Retinoic acid has also been implicated as a morphogen in embryonic development (18). The adverse effects of vitamin A deficiency on reproduction, growth, and the immune response, in all likelihood, are an expression of perturbations in the process of cellular differentiation. 

Figure 4 Reversed-phase HPLC elution profiles of tocopherols (panel A), retinoids (B), and carotenoids (C) present in human plasma (200 pL). Blood was collected 3 h after an oral dose of retinoic acid. The chromatogram was obtained by use of gradient elution (Table 3). Peak identification 2, 4-oxo-retinoic acid 4, retinoyl P-glucuronide 7, retinoic acid 8, retinol 9, retinyl acetate (internal standard) 15, butylated hydroxy toluene 16, y-tocopherol 17, a-tocopherol 18, free bilirubin 19, lutein 20, zeaxanthin 21, 2, 3 -anhydrolutein 22, P-cryptoxanthin 23, lycopene 24, a-carotene 25, P-carotene. (From Ref. 73.)...

The predominant retinoid in the fasting circulation is retinol, all of which is bound to its specific plasma transport protein, retinol-binding protein (RBP) [1,2]. Although retinol accounts for approximately 95 to 99% of all retinoid in the circulation, other retinoids also are present. Fasting human and rodent blood contains very low levels of both sAhtrans- and 13-cw-retinoic acid (approximately 0.2 to 0.7% of those of retinol) [3], as well as low levels of retinyl esters in lipoprotein fractions, particularly very low-density lipoproteins (VLDL) and low density lipoproteins (LDL) [4]. Soluble glucuronides of both retinol and retinoic acid are also detectable in the circulation of humans and rodents [5], as are provitamin A carotenoids like P-carotene... 

Following consumption of a retinoid-rich meal, the circulation can also contain large amounts of retinyl esters in chylomicrons and/or their remnants [6,7]. Postprandial retinyl ester concentrations can easily exceed fasting retinol levels by several fold [7, 8]. Moreover, consumption of a retinoid-rich meal brings about an increase in circulating concentrations of all-trans- and 13-cw retinoic acid and of glucuronides of both retinol and retinoic acid [7, 9]. 

The parent compound in the vitamin A group is called sdl-trans retinol (Fig. lA) [4]. Its aldehyde and acid forms are retinal (Fig. IB) and retinoic acid (Fig. 1C). The active form of vitamin A in vision is ll-cis retinal (Fig. ID), and a therapeutically useful form (accutane, isotretinoin) is l3-cis retinoic acid (Fig. IE). Retinyl palmitate (Fig. IF) is a major storage form, and retinoyl p-glucuronide is a biologically active, relatively non-toxic water-soluble metabolite (Fig. IG). A synthetic aromatic analog (etretin, acitretin), shows therapeutic usefulness (Fig. IH). Finally, p-carotene, a major provitamin A carotenoid, is shown in Figure II. 

Numerous metabolites of retinol or retinoic acid are more polar than retinol or retinoic acid due to additional oxidation of the cyclohexenyl ring, often on carbon 4. Some retinoids, particularly retinoic acid and 4-keto-retinoic acid, may be conjugated with glucuronic acid, forming retinyl- or retinoyl-/3-glucuronide (R5) these metabolites are water-soluble and therefore readily excreted. While some polar and water-soluble retinoids possess bioactivity, most show reduced, or no, activity compared to their precursors. 

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