Retinoyl-/?-glucuronide

The plasma concentration of retinoyl glucuronide is between 5 and 14 mnol per L, and the activity of retinoic acid UDP-glucuronyltransferase increases in vitamin A deficiency, suggesting that glucuronidation may be important... 

The higher concentration reported by Napoli et al. (22) may be due to hydrolysis of the glucuronide metabolite since retinoyl glucuronide is hydrolyzed by acid or base to retinoic acid (33.341. The extraction procedure of Napoli et al. (22) utilized 2N HC1 which could potentially convert most of the retinoyl glucuronide to retinoic acid. Therefore, the concentration of all trans retinoic acid as reported by this assay could represent the sum of these two retinoids, and not that of the free acid (22). Our assay uses less harsh acidic conditions for extraction which should prevent hydrolysis of the glucuronide, resulting in a lower plasma concentration of the all trans isomer as reported by Napoli et al. 22). 

The findings of Fidge et al. (1968) were consistent with earlier observations (Zachman and Olson, 1965 Zachman et al., 1966) that retinoic acid, injected into the portal vein, was rapidly metabolized and excreted in the bile. The labeled compounds found in bile consisted of a mixture of polar metabolites, most of which were more polar than free retinoic acid. One of the metabolites of retinoic acid in bile has been identified as retinoyl -glucuronide (Dunagin et al., 1965 Zile et al., 1980, 1982a Swanson et al., 1981). Other polar metabolites account for most of the radioactivity in bile after administration of labeled retinoic acid to rats (Zile et al., 1980, 1982a) one of these has been identified as a taurine conjugate of a retinoic acid metabolite (Skare et al., 1982). 

At normal levels of intake, most retinol is catabolized by oxidation to retinoic acid and excreted in the bile as retinoyl glucuronide. As the liver concentration or retinol rises above 70 LLmol/kg, there is microsomal cytochrome P -dependent oxidation, leading to a number of polar metabolites, which are excreted in the urine and bile. At high intakes this pathway becomes saturated, and excess retinol is toxic because there is no further capacity for its catabolism and excretion. 

Figure 5. PBPK model for all-rmn -retinoyl glucuronide. Rounded box indicates the submodel depicted in Figure 3 (all-rran5-4-oxoretinoic acid). Abbreviations are as listed in the legend to Figure 1.

Another metabolite, which may be very important, is retinoyl 3-glucuronide. i11 s... 

Sidell N, Sawatsri S, Connor Ml, Barua AB, Olson lA, and Wada RK (2000) Pharmacokinetics of chronically administered all-frans-retinoyl-heta-glucuronide in mice. Biochimica etBiophysica Acta 1502, 264-72. 

Barua AB (1997) Retinoyl beta-glucuronide a biologically active form of vitamin A Nutrition Reviews 55, 259-67. 

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]. 

Retinoic acid from the intestinal mucosa is transported bound to serum albumin via the portal vein. Retinoic acid cannot be significantly reduced to retinal but is rapidly metabolized in tissue, such as Uver, to yield more polar catabohtes (e.g., 5,6-epoxyretinoic acid) and conjugates, such as retinoyl p-glucuronide, that are excreted. A small amount of retinoic acid undergoes enterohepatic circulation after intestinal hydrolysis of the glucuronide is excreted in the bile. 

Topical retinoids—tretinoin, adapalene, tazarotene, and in some countries topical isotretinoin, motretinide, retinaldehyde, and retinoyl-/S-glucuronide —should be used as first-line therapy for mild to moderate inflammatory acne and comedonal acne. They are also preferred agents for maintenance therapy to minimize antibiotic use in acne therapy. To optimize efficacy in moderate inflammatory acne, topical retinoids should be combined with topical antibiotics or BP0.2T33... 

Retinoyl-/3-glucuronide is a naturally occurring, biologically active metabolite of vitamin A. A 0.16% retinoyl- 8-glucuronide cream has been shown to be effective against inflammatory and noninflammatory acne lesions with comparable efficacy to tretinoin, but with less irritation potential and comparatively fewer other adverse effects than with tretinoin. 

Goswami BC, Baishya B, Barua AB, Olson JA. Topical retinoyl beta-glucuronide is an effective treatment of mild to moderate acne vulgaris in Asian-Indian patients. Skin Pharmacol Appl Skin Physiol 1999 12 167-173. 

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