Glucuronidation and isomerization of all-trans- and 13-CIS-retinoic acid by liver microsomes of phenobarbital- or 3-methylcholanthrene-treated rats

Sass, Jörn Oliver; Forster, Adelheid; Bock, Karl Walter; Nau, Heinz

doi:10.1016/0006-2952(94)90179-1

Cited by 29 publications

(12 citation statements)

References 26 publications

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“…Although the glucuronidation of RA by rat liver microsomal preparations has been demonstrated by sever al investigators [19,[49][50][51], the UDP-glucuronosyltransferase that acts on RA has not been identified [52]. Glucuronides, being wa ter-soluble, arc usually excreted rapidly in the bile and urine, and consequently show very low plasma concentrations [53].…”

Section: Discussionmentioning

confidence: 99%

Percutaneous Absorption, Excretion and Metabolism of All-trans-Retinoyl β-Glucuronide and of AII-trans-Retinoic Acid in the Rat

Barua

Olson²

1996

Skin Pharmacol Physiol

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The purpose of these studies was to compare directly the percutaneous absorption, excretion and metabolism of all-trans-retinoyl Β-glucuronide (RAG), a nontoxic retinoid, with all-trans-retinoic acid (RA) in the rat. Previously, it was demonstrated that topical treatment of human acne with either RAG or RA in cream resulted in a significant reduction of lesions. Whereas 0.1 % RA showed adverse effects, concentrations of RAG up to 2.4% did not cause any adverse reactions. In the present studies, radiolabeled RAG or RA, dispersed in a water-based cream, was applied to the shaved dorsal skin of vitamin A-sufficient rats. Both RAG and RA were absorbed from the skin in a similar way. In both cases, radioactivity peaked in the plasma within 2-4 h and within the liver at 4-12 h. During a 7-day period, the overall excretion of radioactivity derived from RA and RAG in the feces and urine were similar, e.g. 17 and 12%, respectively. It is concluded that: (1)the transport, metabolism and excretion of topically applied radioactive RA and RAG are similar, although not identical, in the rat and (2) the toxic skin manifestations induced by RA but not by RAG cannot be attributed to major differences in their overall absorption, metabolism and excretion.

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Section: Discussionmentioning

confidence: 99%

Percutaneous Absorption, Excretion and Metabolism of All-trans-Retinoyl β-Glucuronide and of AII-trans-Retinoic Acid in the Rat

Barua

Olson²

1996

Skin Pharmacol Physiol

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“…To our knowledge, CYP1A1 has not been examined in the context of RA hydroxylation, but it catalyzes the 4‐hydroxylation of 13‐ cis ‐ and all‐ trans ‐retinaldehyde [35]. In rats, TCBP, TCDD, and 3‐methylcholanthrene increased conjugation of RA by UDP‐glucuronyltransferase [24, 36–39]. Several inducible UDP‐glucuronyltransferase isoforms have been identified in fish liver [40], but their activity regarding RA conjugation has not been established.…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3′,4,4′‐tetrachlorobiphenyl

Boyer

Ndayibagira

Spear

2000

Enviro Toxic and Chemistry

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Abstract-Extremely low stores of vitamin A have been reported in fish and birds inhabiting regions contaminated by coplanar polychlorinated biphenyls (PCBs) and other organochlorines, suggesting many possible effects on retinoid biochemical pathways. Metabolic imbalances associated with biologically active retinoids (e.g., retinoic acid) could be associated with teratogenesis, edema, growth inhibition, reproductive impairment, immunosuppression, and susceptibility to cancer. Sexually mature brook trout were injected intraperitoneally with the coplanar PCB 3,3Ј,4,4Ј-tetrachlorobiphenyl (TCBP) and again 4 weeks later. At 8 weeks, retinoic acid metabolism was measured in liver microsomes. To our knowledge, retinoic acid conjugation by UDP-glucuronyltransferase is described here for the first time in fish. A substantial rate of glucuronidation was detected in the microsomes from control brook trout, which tended to increase over the dose range of TCBP. Glucuronidation was significantly greater in fish receiving the 10 g/ g body weight dose level. Metabolism through the cytochrome P450 system was also dose-dependent, resulting in significantly greater production of 4-hydroxyretinoic acid at the 10 g/g dose level. In contrast, subsequent oxidation to 4-oxo-retinoic acid was greatest at the 1 g/g dose level and did not increase further at higher doses. Liver stores of dehydroretinyl palmitate/oleate were significantly decreased at the 5 and 10 g/g dose levels.

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“…␤ -Glucuronides of all-trans retinol and of all-trans retinoic acid have been shown to be formed by liver microsomes in vitro ( 43 ) and in vivo ( 25,42,45 ) by the action of microsomal UDP-glucuronosyl transferase ( 45 ). Retinoid ␤ -glucuronides have been detected in various mouse tissues ( 44 ) and in the circulation ( 46 ), suggesting that these compounds could represent a water-soluble transport form of vitamin A channeling retinol through the ER or through the circulation.…”

Section: Es22 Is Predominantly Expressed In Hepatocytesmentioning

confidence: 99%

Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver

Schreiber

Taschler

Wolinski

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org retinol is reesterifi ed ( 3-5 ) for the incorporation into chylomicrons and secreted ( 6 ). In the circulation, chylomicrons are depleted from triglycerides by lipoprotein lipase and are thereby transformed to chylomicron remnants ( 7 ). These remnants acquire apolipoprotein E and are then cleared mostly by parenchymal cells of the liver (i.e., hepatocytes) ( 8-10 ). In hepatocytes, REs are hydrolyzed, and unesterifi ed retinol is associated with retinol-binding protein 4 (RBP4) for secretion ( 11,12 ) or transferred to hepatic stellate cells for storage ( 10,13,14 ). These stellate cells store most of the total body vitamin A reserves ( ‫ف‬ 80%) in the form of retinyl palmitate in cytosolic lipid droplets ( 14 ).According to the body's demand, stored retinoids are released from the liver to facilitate a constant supply. In the circulation, the biologically inactive retinol is transported bound to RPB4 and delivered to target tissues. There, retinol is converted into its biologically active metabolites 11-cis retinaldehyde and retinoic acids, which act as h acceptor in the visual cycle and as ligand of nuclear receptors, respectively.The dynamic balance between synthesis and hydrolysis of RE determines the concentration of retinol in the circulation and also the availability of retinol for conversion in active metabolites in various cell types. Retinol is esterifi ed by the action of acyl-CoA:retinol acyltransferase (ARAT) or lecithin:retinol acyltransferase (LRAT) for storage in lipid droplets. Much work has focused on the understanding of how REs are released from lipid droplets and which Abstract Excess dietary vitamin A is esterifi ed with fatty acids and stored in the form of retinyl ester (RE) predominantly in the liver. According to the requirements of the body, liver RE stores are hydrolyzed and retinol is delivered to peripheral tissues. The controlled mobilization of retinol ensures a constant supply of the body with the vitamin. Currently, the enzymes catalyzing liver RE hydrolysis are unknown. In this study, we identifi ed mouse esterase 22 (Es22) as potent RE hydrolase highly expressed in the liver, particularly in hepatocytes. The enzyme is located exclusively at the endoplasmic reticulum (ER), implying that it is not involved in the mobilization of RE present in cytosolic lipid droplets. Nevertheless, cell culture experiments revealed that overexpression of Es22 attenuated the formation of cellular RE stores, presumably by counteracting retinol esterifi cation at the ER. Es22 was previously shown to form a complex with ␤ -glucuronidase (Gus). Our studies revealed that Gus colocalizes with Es22 at the ER but does not affect its RE hydrolase activity. Interestingly, however, Gus was capable of hydrolyzing the naturally occurring vitamin A metabolite retinoyl ␤ -glucuronide. In conclusion, our observations implicate that both Es22 and Gus play a role in liver retinoid metabolism. -Schreiber, R., U. Taschler

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Glucuronidation and isomerization of all-trans- and 13-CIS-retinoic acid by liver microsomes of phenobarbital- or 3-methylcholanthrene-treated rats

Cited by 29 publications

References 26 publications

Percutaneous Absorption, Excretion and Metabolism of All-<i>trans</i>-Retinoyl β-Glucuronide and of AII-<i>trans</i>-Retinoic Acid in the Rat

Percutaneous Absorption, Excretion and Metabolism of All-<i>trans</i>-Retinoyl β-Glucuronide and of AII-<i>trans</i>-Retinoic Acid in the Rat

Dose‐dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3′,4,4′‐tetrachlorobiphenyl

Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver

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