Location of Repository

The Biological Effects of Novel Synthetic Retinoids

By ROWLAND JOHN JAMES BUDGE

Abstract

Naturally occurring Retinoids are known to play a role in many developmental processes in the early embryo as well as being a potent tool for in vitro differentiation of stem cells. The exogenous application of these naturally occurring retinoids as well as some of their synthetic analogs has been shown to yield digit duplication phenotypes and facial phenotypes in the model system of chick. It is not however always appreciated that these naturally occurring retinoids are highly susceptible to isomerisation and that these isomers have different biological activity. Due to this EC23 and EC19, synthetic analogs of these retinoids which are not able to be isomerised, have been synthesized. These two compounds until now have not been tested in vivo. \ud We showed that both EC23 and EC19 are able to yield retinoid phenotypes in the model system of chick. We also showed that EC23 is far more toxic than EC19 or ATRA, while being far more able to create retinoid limb phenotypes at lower concentrations. EC19 in this investigation is shown to produce very few retinoid limb phenotypes in comparison, but is able to yield a far higher frequency of retinoid facial phenotypes.\ud In conclusion this investigation shows the ability of EC23 to emulate known ATRA limb phenotypes at much lower concentrations. EC19 is shown to yield less limb phenotypes possibly due to its similarities in structure to 13-cis RA, EC19 is also shown to yield facial phenotypes more frequently than EC23 or ATRA.\u

Topics: Retinoids
Year: 2010
OAI identifier: oai:etheses.dur.ac.uk:781
Provided by: Durham e-Theses

Suggested articles

Preview

Citations

  1. (1992). 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor doi
  2. (1993). 9-cis-retinoic acid, a potent inducer of digit pattern duplications in the chick wing bud.”
  3. (1996). A decade of molecular biology of retinoic acid receptors.”
  4. (2000). A et al. “Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism.” doi
  5. (1987). A human retinoic acid receptor which belongs to the family of nuclear receptors.” doi
  6. (1999). A molecular basis for retinoic acidinduced axial truncation.” doi
  7. (1971). A new procedure for whole mount alcian staining of the cartilage skeleton of chicken embryos, adapted to the clearing procedure in potassium hydroxide.” Acta Morph. Ne Scand,
  8. (1984). A novel retinol-binding protein from rat. Purification and partial characterization.”
  9. (1985). A quantitative analysis of the effect of retinoic acidon pattern formation in the developing chick doi
  10. (1951). A series of normal stages in the development of the chick embryo.” doi
  11. (1999). Abnormal anteroposterior and dorsoventral patterning of the limb bud in the absence of retinoids.” doi
  12. (2003). About face: signals and genes controlling jaw patterning and identity in vertebrates.” doi
  13. (1984). Analysis of upperbeak defects in chicken embryos following treatment with retinoic acid.”
  14. (2001). and Jill A Helms. “Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8
  15. (1975). Binding of retinol to isolated retinal pigment epithelium in the presence and absence of retinol-binding protein.” doi
  16. (2000). Biosynthesis of all-transretinoic retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation byhuman P-450 cytochromes.” Drug Metab.
  17. (1997). cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450 doi
  18. (1994). Clinical pharmacology of all-trans retinoic acid.” doi
  19. (2002). Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles.” doi
  20. (1997). CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family.” doi
  21. (1998). Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid.” doi
  22. (1992). Development of the spatial pattern of retinoic acid receptor-beta transcripts in embryonic chick facial primordia.” doi
  23. (1997). Differential expression of transcripts encoding retinoid binding proteins and retinoic acid receptors during placentation of the mouse.” doi
  24. (1999). Distinct Roles for Cellular Retinoic Acid-binding Proteins I and II in Regulating Signaling by Retinoic Acid.” doi
  25. (1991). Effects of isotretinoin (13-Cisretinoic acid) on the development of mouse limbs in vivo and in vitro.” Developmental Pharmacology and Toxicology, doi
  26. (1995). Enhanced potency of 9-cis versus all-trans-retinoic acid to induce the differentiation of human neuroblastoma cells.” differentiation, doi
  27. (1997). Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.” doi
  28. (1993). Experimental analysis of the control of expression of the homeobox-gene Msx 1 in the developing limb and face.”
  29. (1998). Expression of cytochrome P450 RAI (CYP26) in human fetal hepatic and cephalic tissues.” doi
  30. (1999). Expression of retinoic acid 4-hydroxylase (CYP26) during mouse and Xenopus laevis embryogenesis.” doi
  31. (1995). Expression of the chicken retinoid X receptor-gamma gene in migrating cranial neural crest cells.” Anat. doi
  32. (1994). Expression patterns of the bone morphogenetic protein genes doi
  33. (2007). Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb.” doi
  34. (2004). Feedback mechanisms regulate retinoic acid production and degradation in the zebrafish embryo.” Mech Dev.
  35. (2002). FGF Signaling regulates expression of doi
  36. (1995). gene expression during chick mandibular morphogenesis.” doi
  37. (2002). Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development.” doi
  38. (1999). Hindbrain respecification in the retinoid-deficient quail.” doi
  39. (2000). Human cytochrome P-450 metabolism of retinals to retinoic acids.”
  40. (1987). Identification of a receptor for the morphogen retinoic acid.” doi
  41. (1996). Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase.” doi
  42. (1995). Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.” doi
  43. (2008). Integration of growth and specification in chick wing.” doi
  44. (1996). Liarozole inhibits human epidermal retinoic acid 4-hydroxylase activity and differentially augments human skin responses to retinoic acid and retinol in vivo.” doi
  45. (2002). Liarozole Markedly Increases all trans-Retinoic Acid Toxicity doi
  46. (1998). Ligand- and DNA-induced dissociation of
  47. (1982). Local application of retinoic acid to the limb bud mimics the action of the polarizing region.” Nature (Lond.)., doi
  48. (2001). Localization of the RAR interaction domain of cellular retinoic acid binding protein-II.” doi
  49. (2003). Mesenchymal/epithelial regulation of retinoic acid signaling in the olfactory placode.” doi
  50. (1997). Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos.” doi
  51. (1980). Metabolism of all-trans-retinoic acid in hamster liver microsomes: oxidation of 4-hydroxy- to 4-keto-retinoic acid.” doi
  52. (2004). Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1.” Drug Metab. doi
  53. (1984). Micro-controlled release of biologically active compounds in chick embryos: beads of 200/xm diameter for the local release of retinoids.” doi
  54. (1998). Mouse P450RAI (CYP26) expression and retinoic acid-inducible retinoic acid metabolism in F9 cells are regulated by retinoic acid receptor gamma and retinoid doi
  55. (1997). Multiple factors contribute to the toxicity of the aromatic retinoid, TTNPB (Ro 13-7410) : Binding affinities and disposition.” Toxicology and applied pharmacology 142 doi
  56. (1995). Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life?” doi
  57. (1990). Nuclear receptor that identifies a novel retinoic acid response pathway.” doi
  58. (1971). Positional information and pattern doi
  59. (1975). Positional signalling and specification of digits in chick limb morphogenesis. doi
  60. (2007). RALDHindependent generation of retinoic acid during vertebrate embryogenesis by CYP1B1.” doi
  61. (1998). Regional pattern of retinoid X receptor alpha gene expression in the central nervous system of the chicken embryo and its up-regulation by exposure to 9-cis retinoic acid.” doi
  62. (2005). Regulation of a highly specific retinoic acid-4-hydroxylase (CYP26A1) enzyme and all-trans-retinoic acid metabolism in human intestinal, liver, endothelial, and acute promyelocytic leukemia cells.” doi
  63. (1997). Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb.”
  64. (1997). Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (Raldh-2) gene during mouse development.” doi
  65. (1989). Retinoic acid application to chick wing buds leads to a dose-dependent reorganization of the apical ectodermal ridge that is mediated by the mesenchyme.”
  66. (1999). Retinoic acid hydroxylase (CYP26) is a key enzyme in neuronal differentiation of embryonal carcinoma cells.” doi
  67. (1994). Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling.” doi
  68. (1996). Retinoic acid signaling is required during early chick limb development.”
  69. (2003). Retinoic acid signalling centres in the avian embryo identified by sites of expression of synthesising and catabolising enzymes.” Dev. doi
  70. (1995). Retinoic acid synthesizing enzymes in the embryonic and adult vertebrate.” doi
  71. (2002). Retinoid signalling in the development of the central nervous system.” doi
  72. (1992). Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.” doi
  73. (1998). Retinoids and mouse placentation.” doi
  74. (1991). Retinoids and their receptors in differentiation, embryogenesis,
  75. (1995). Retinol in Avian oogenesis: molecular properties of the carrier protein.” doi
  76. (1968). Retinol-binding protein: the transport protein for vitamin A in human plasma.” doi
  77. (2000). Reza Zolfaghari, and A Catharine Ross. “Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats.” doi
  78. (2002). Stimulation of retinoic acid production and growth by ubiquitouslyexpressed alcohol dehydrogenase doi
  79. (1985). Studies on the Mechanism of Retinoid-induced Pattern Duplications in the Early Chick Limb Bud: Temporal and Spatial Aspects.” doi
  80. (2008). Synthesis and evaluation of synthetic retinoid derivatives as inducers of stem cell differentiation.” doi
  81. (1998). The cloning and characterization of a novel cytochrome P450 family, CYP26, with specificity toward retinoic acid.” doi
  82. (1997). The DNA Binding Pattern of the Retinoid X Receptor Is Regulated by Ligand-dependent Modulation of Its Oligomeric doi
  83. (1983). The effect of local application of retinoic acid to the anterior margin of the developing chick limb.”
  84. (1995). The function and evolution of Msx genes: pointers and paradoxes.” doi
  85. (1995). The nuclear receptor superfamily: the second decade.” doi
  86. (1994). The Retinoids: Biology, Chemistry and Medicine.
  87. (1988). The steroid and thyroid hormone receptor superfamily.” doi
  88. (1998). The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction.”
  89. (2004). Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester.” doi
  90. (1993). Transport and uptake of retinol during chicken oocyte growth.” doi
  91. (2002). Unique property of some synthetic retinoids: activation of the aryl hydrocarbon receptor pathway.” doi
  92. (2003). Upper beak truncation in chicken embryos with the cleft primary palate mutation is due to an epithelial defect in the frontonasal mass.” doi
  93. (2000). Vitamin A deficiency results in the dose-dependent acquisition of anterior character and shortening of the caudal hindbrain of the rat embryo.” doi
  94. (1996). Vitamin A-deficient quail embryos have half a hindbrain and other neural defects.” doi
  95. (1960). Vitamin A1 Aldehyde in Hen's Eggs.” doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.