Retinoic Acid

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J. L. Napoli - One of the best experts on this subject based on the ideXlab platform.

  • Microsomal Retinoic Acid metabolism. Effects of cellular Retinoic Acid-binding protein (type I) and C18-hydroxylation as an initial step.
    The Journal of biological chemistry, 1994
    Co-Authors: P D Fiorella, J. L. Napoli

    This report extends our observation that cellular Retinoic Acid-binding protein type I (CRABP) serves as substrate for Retinoic Acid metabolism by testis microsomes. Retinoic Acid bound to excess CRABP was metabolized at 70% of the unbound Retinoic Acid rate with testis microsomes and at the same rates as unbound Retinoic Acid with kidney and lung microsomes. Chromatography of testis, lung, kidney, and liver microsomal incubations provided two sets of metabolites each, P1 and P2. The composition of P2 was characteristic of the individual tissue. CRABP had modest quantitative affects on P2 composition, but did not affect P2 qualitatively. Retinoids bound to CRABP, isolated from a testis microsomal incubation, consisted of 50% Retinoic Acid, 32% P1 and 17% P2, suggesting that CRABP may bind Retinoic Acid metabolites in vivo. The effect of CRABP on the rate of metabolism was retinoid specific. Two major components of P2, 4-hydroxy-Retinoic Acid and 4-oxo-Retinoic Acid, when bound to CRABP were metabolized slowly, if at all, by testis microsomes, in contrast to CRABP-bound Retinoic Acid which had an elimination t1/2 of 40 min. Unbound Retinoic Acid, 4-hydroxy-Retinoic Acid, and 4-oxo-Retinoic Acid had elimination t1/2 values of 35, 40, and 9 min, respectively. Reduced metabolism of CRABP-bound C4-derivatized retinoids suggests pathways of Retinoic Acid metabolism besides the one initiated by C4-hydroxylation. This was corroborated by identification of 18-hydroxy-Retinoic Acid as a testis, lung, and liver microsomal Retinoic Acid metabolite. Ketoconazole inhibited the metabolism by testis microsomes of free and CRABP-bound Retinoic Acid with IC50 values of 2 and 0.7 microM, respectively, denoting catalysis by cytochrome P-450. These results indicate that cloistering Retinoic Acid in CRABP, while permitting metabolism, may operate throughout CRABP-expressing tissues as a mechanism of controlling the concentrations of free Retinoic Acid.

  • Biosynthesis and Metabolism of Retinoic Acid: Roles of CRBP and CRABP in Retinoic Acid: Roles of CRBP and CRABP in Retinoic Acid Homeostasis
    Journal of Nutrition, 1993
    Co-Authors: J. L. Napoli

    The enzymes that constitute the pathway of Retinoic Acid biosynthesis and metabolism may recognize retinoid binding proteins as effectors and substrates. Apocellular retinol-binding protein (CRBP) stimulates a bile-salt independent membrane-bound retinyl ester hydrolase resulting in the hydrolysis of endogenous retinyl esters and the formation of holoCRBP. HoloCRBP delivers retinol to a microsomal nicotin-amide-adenine dinucleotide phosphate-dependent dehydrogenase, protects it from artifactual oxidation and denies enzymes that cannot recognize the binding protein access to retinol. The retinal synthesized may be transferred from the microsomes to the cytosol by CRBP. A cytosolic retinal dehydrogenase has been purified that produces Retinoic Acid from retinal generated by microsomes in the presence of CRBP and from the complex CRBP-retinal itself. Thus, CRBP(type I) seems to channel retinoids through the reactions of Retinoic Acid synthesis via a series of protein-protein interactions. Cellular Retinoic Acid-binding protein (type I) facilitates Retinoic Acid metabolism by sequestering it and by acting as a low Km substrate, thereby also modulating the steady-state concentrations of Retinoic Acid.

  • Expression of cellular Retinoic Acid binding protein (CRABP) in Escherichia coli. Characterization and evidence that holo-CRABP is a substrate in Retinoic Acid metabolism.
    The Journal of biological chemistry, 1991
    Co-Authors: P D Fiorella, J. L. Napoli

    Abstract Cellular Retinoic Acid binding protein (CRABP) has been expressed efficiently in Escherichia coli from the cDNA of bovine adrenal CRABP and characterized, especially with respect to affinity for endogenous retinoids and a role for it in Retinoic Acid metabolism. The purified E. coli-expressed CRABP was similar to authentic mammalian CRABP in molecular weight (approximately 14,700), isoelectric point (4.76), absorbance maxima (apo-CRABP, 280 nm; holo-CRABP, 350 and 280 nm with the ratio A350/A280 = 1.8), and in fluorescence excitation (350 nm) and emission spectra (475 nm). The equilibrium dissociation constant, Kd, of E. coli-derived CRABP and all-trans-Retinoic Acid was 10 +/- 1 nM (mean +/- S.D., n = 4) by retinoid fluorescence and 7 +/- 1 nM (mean +/- S.D., n = 3) by quenching of protein fluorescence, but neither retinol nor retinal bound in concentrations as high as 7 microM. All-trans-cyclohexyl ring derivatives of Retinoic Acid (3,4-didehydro-, 4-hydroxy-, 4-oxo-, 16-hydroxy-4-oxo-, 18-hydroxy-) had affinities similar to that of all-trans-Retinoic Acid, whereas 13-cis-Retinoic Acid and 4-oxo-13-cis-Retinoic Acid had approximately 25-fold lower affinity. Holo-CRABP was a substrate for Retinoic Acid catabolism in rat testes microsomes by three criteria: 1) the rate of Retinoic Acid metabolism with CRABP in excess of Retinoic Acid exceeded the rate supported by the free Retinoic Acid; 2) increasing the apo-CRABP did not decrease the rate as predicted if free Retinoic Acid were the only substrate; and 3) holo-CRABP had a lower Michaelis constant (1.8 nM) for Retinoic Acid elimination than did free Retinoic Acid (49 nM). These data indicate a direct role for CRABP in Retinoic Acid metabolism and suggest a mechanism for discriminating metabolically between all-trans- and 13-cis-retinoids.

Andrew D.j. Pearson - One of the best experts on this subject based on the ideXlab platform.

  • Gene expression and neuroblastoma cell differentiation in response to Retinoic Acid: differential effects of 9-cis and all-trans Retinoic Acid.
    European Journal of Cancer, 1995
    Co-Authors: Christopher P.f. Redfern, Penny E. Lovat, A. J. Malcolm, Andrew D.j. Pearson

    Retinoic Acid has considerable potential for the chemoprevention and chemotherapy of cancer. Neuroblastoma cells differentiate in response to Retinoic Acid in vitro, an observation that has led to clinical trials using either the 13-cis or all-trans isomers of Retinoic Acid. We review the effects of Retinoic Acid on neuroblastoma, and the potential involvement of nuclear Retinoic Acid receptors (RARs) and retinoid X receptors (RXRs). 9-cis Retinoic Acid is a ligand for RXRs, and we review recent data on the differential effects of 9-cis and all-trans Retinoic Acid on neuroblastoma differentiation and proliferation in vitro, and possible mechanisms of action via hetero- and homodimers of RARs and RXRs. Although there is uncertainty whether or not 9-cis Retinoic Acid produces its biological effects primarily via RXR homodimers, in vitro data suggest that this isomer of Retinoic Acid or stable analogues may have considerable potential for the treatment of resistant, disseminated neuroblastoma.

  • Differential effects of 9-cis and all-trans Retinoic Acid on the induction of Retinoic Acid receptor-beta and cellular Retinoic Acid-binding protein II in human neuroblastoma cells.
    Biochemical Journal, 1994
    Co-Authors: Christopher P.f. Redfern, Penny E. Lovat, A. J. Malcolm, Andrew D.j. Pearson

    The objective of this study was to compare the properties of 9-cis and all-trans Retinoic Acid with respect to the induction of expression of Retinoic Acid receptor beta (RAR-beta) and cellular Retinoic Acid-binding protein (CRABP) II in human neuroblastoma SH SY 5Y cells. RAR-beta and CRABP II mRNA was induced by both all-trans and 9-cis Retinoic Acid in SH SY 5Y cells. Induction was rapid, detectable within 2-4 h, and inhibited by actinomycin D. Time-courses of induction for RAR-beta and CRABP II differed: RAR-beta mRNA levels reached a maximum 4-6 h after adding all-trans or 9-cis Retinoic Acid, whereas CRABP II mRNA levels increased over at least 18 h. These differences were attributed to the longer half-life of CRABP II mRNA (20 h) compared with RAR-beta mRNA (3.9 h). The dose-response characteristics of all-trans and 9-cis Retinoic Acid were different: all-trans was effective at nanomolar concentrations, whereas 10-fold higher levels of 9-cis Retinoic Acid were required to achieve comparable induction of RAR-beta and CRABP II. Conversely, at high concentrations, 9-cis Retinoic Acid gave a greater induction of RAR-beta and CRABP II than all-trans. The induction of RAR-beta and CRABP II by all-trans Retinoic Acid was maintained in the subsequent absence of all-trans Retinoic Acid, whereas induction by 9-cis Retinoic Acid was dependent on its continued presence in the culture medium. These results suggest that, at high concentrations, 9-cis Retinoic Acid may produce its transcriptional effects via retinoid X receptor (RXR) homodimers. This has implications for the cellular functions of 9-cis Retinoic Acid and its use as a biological response modifier.

Heinz Nau - One of the best experts on this subject based on the ideXlab platform.

  • comparative teratology and transplacental pharmacokinetics of all trans Retinoic Acid 13 cis Retinoic Acid and retinyl palmitate following daily administrations in rats
    Toxicology and Applied Pharmacology, 1994
    Co-Authors: Michael D Collins, Georg Tzimas, Hans Hummler, H Burgin, Heinz Nau

    Abstract The retinoids are teratogenic in a wide variety of species. In the rat, 13- cis -Retinoic Acid and retinyl palmitate are significantly less potent teratogens than all- trans -Retinoic Acid. This investigation questioned whether differing teratogenic potencies of these moieties can be correlated with the concentrations of these drugs and/or metabolites in the embryonic compartment. Approximately equipotent teratogenic doses of these three retinoids were administered and the pharmacokinetics in maternal plasma and embryo of the most prevalent vitamin A metabolites were measured. The glucuronides of the respective retinoids were the predominant metabolites in the maternal plasma, but were not detected in the embryo. Also, the transport of 13- cis -Retinoic Acid across the placenta occurred to a much lesser extent than the transport of all- trans -Retinoic Acid. Administration of either all- trans - or 13- cis -Retinoic Acid causes a depression in the endogenous retinol concentration. This depression is more pronounced in the maternal plasma than in the embryo. The depression of the retinol level in both plasma and embryo after 13- cis -Retinoic Acid administration (75 mg/kg/day) was greater than the depression after all- trans -Retinoic Acid (6 mg/kg/day), corroborating the inferential teratological data that the 13- cis -Retinoic Acid dose was more embryotoxic than the all- trans -Retinoic Acid dose. Although the dose of all- trans -Retinoic Acid was less embryotoxic than that of either 13- cis -Retinoic Acid or retinyl palmitate, the embryonic exposure to all- trans -Retinoic Acid was considerably larger, as determined by maximum concentration or area under the concentration-versus-time curve, after administration of all- trans -Retinoic Acid than after either retinyl palmitate or 13- cis -Retinoic Acid application. These results suggest that embryonic retinoids other than all- trans -Retinoic Acid-including the administered substances themselves-are important in the teratogenic process induced by 13- cis -Retinoic Acid and retinyl palmitate.

Gregg Duester - One of the best experts on this subject based on the ideXlab platform.

  • Retinoic Acid synthesis and signaling during early organogenesis
    Cell, 2008
    Co-Authors: Gregg Duester

    Retinoic Acid, a derivative of vitamin A, is an essential component of cell-cell signaling during vertebrate organogenesis. In early development, Retinoic Acid organizes the trunk by providing an instructive signal for posterior neuroectoderm and foregut endoderm and a permissive signal for trunk mesoderm differentiation. At later stages, Retinoic Acid contributes to the development of the eye and other organs. Recent studies suggest that Retinoic Acid may act primarily in a paracrine manner and provide insight into the cell-cell signaling networks that control differentiation of pluripotent cells.

  • Retinoic Acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of Retinoic Acid synthesis.
    Molecular and cellular biology, 1991
    Co-Authors: Gregg Duester, Mary Lou Shean, M S Mcbride, M J Stewart

    Abstract Retinoic Acid regulation of one member of the human class I alcohol dehydrogenase (ADH) gene family was demonstrated, suggesting that the retinol dehydrogenase function of ADH may play a regulatory role in the biosynthetic pathway for Retinoic Acid. Promoter activity of human ADH3, but not ADH1 or ADH2, was shown to be activated by Retinoic Acid in transient transfection assays of Hep3B human hepatoma cells. Deletion mapping experiments identified a region in the ADH3 promoter located between -328 and -272 bp which confers Retinoic Acid activation. This region was also demonstrated to confer Retinoic Acid responsiveness on the ADH1 and ADH2 genes in heterologous promoter fusions. Within a 34-bp stretch, the ADH3 Retinoic Acid response element (RARE) contains two TGACC motifs and one TGAAC motif, both of which exist in RAREs controlling other genes. A block mutation of the TGACC sequence located at -289 to -285 bp eliminated the Retinoic Acid response. As assayed by gel shift DNA binding studies, the RARE region (-328 to -272 bp) of ADH3 bound the human Retinoic Acid receptor beta (RAR beta) and was competed for by DNA containing a RARE present in the gene encoding RAR beta. Since ADH catalyzes the conversion of retinol to retinal, which can be further converted to Retinoic Acid by aldehyde dehydrogenase, these results suggest that Retinoic Acid activation of ADH3 constitutes a positive feedback loop regulating Retinoic Acid synthesis.

Robert M Russell - One of the best experts on this subject based on the ideXlab platform.

  • formation of all trans Retinoic Acid and 13 cis Retinoic Acid from all trans retinyl palmitate in humans
    Journal of Nutritional Biochemistry, 1991
    Co-Authors: Guangwen Tang, Robert M Russell

    Abstract Increments of levels of both 13-cis- and all-trans-Retinoic Acid in human plasma were observed after either a physiologic or a pharmacologic oral dose of all-trans-retinyl palmitate. Subjects receiving a physiologic dose showed mean ± SEM plasma rises over baseline as follows: all-trans-Retinoic Acid = 1.1 ± 0.3 nmol/L and 13-cis-Retinoic Acid = 4.7 ± 1.1 nmol/L, which represented increases in 1.3 fold and 1.9 fold over fasting plasma levels. Those receiving a pharmacologic dose showed mean ± SEM plasma rises over baseline as follows: all- trans -Retinoic Acid = 11.5 ± 2.6 nmol/L and 13-cis -Retinoic Acid = 37.5 ± 6.1 nmol/L, which represented increases of 3.9-fold and 8.4-fold over fasting plasma levels. Moreover, areas under the curve of the means of all-trans- and 13-cis-Retinoic Acid over 24 hours showed that larger amounts of 13-cis-Retinoic Acid appear in the circulation than all-trans-Retinoic Acid after feeding all-trans-retinyl palmitate. The increase in Retinoic Acid in the circulation may be an important source of Retinoic Acid for some organs.