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Part of the book series: MCBU Molecular and Cell Biology Updates ((MCBU))

Abstract

Use of retinoid binding proteins as substrates for identifying enzymes of retinoid metabolism has revealed compelling new candidates (e.g. lecitin:retinol acyltransferase [LRAT], intestinal microsomal retinal reductase, retinol dehydrogenase [RDH]), and has redirected attention away from historical candidates (intestinal cytosolic retinal reductase, alcohol dehydrogenase [ADH]), which, at any rate, had not been well characterized with respect to retinoid metabolism. The use by specific enzymes of retinol complexed with cellular retinol binding protein (CRBP) provides potential insight into the mechanisms of intracellular retinol access and of imposing specificity on retinoid metabolism. These data also suggest why relatively rapid depletion of retinol does not occur in vivo via enzymes generally associated with xenobiotic metabolism, such as myriad cytochrome P-450 s and ADHs, despite their activities with “free” retinol in vitro.

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References

  1. Ong DE, MacDonald PN, Gubitosi AM (1988) Esterification of retinol in rat liver: possible participation by cellular retinol-binding protein and cellular retinol binding-protein II. J Biol Chem 263: 5789–5796

    PubMed  CAS  Google Scholar 

  2. Yost RW, Harrison EH, Ross AC (1988) Esterification by rat liver microsomes of retinol bound to cellular retinol-binding protein. J Biol Chem 263: 18693–18701

    PubMed  CAS  Google Scholar 

  3. Shi YQ, Furuyoshi S, Hubacek I, Rando RR (1993) Affinity labeling of lecithin retinol acyltransferase. Biochemistry 32: 3077–3080

    Article  PubMed  CAS  Google Scholar 

  4. Ruiz A, Winston A, Lim Y-H, Gilbert BA, Rando RR, Bok D (1999) Molecular and biochemical characterization of lecithin retinol acyltransferase (LRAT). J Biol Chem 274: 3834–3841

    Article  PubMed  CAS  Google Scholar 

  5. Boerman MHEM, Napoli JL (1995) Characterization of a microsomal retinol dehydrogenase: a short-chain alcohol dehydrogenase with integral and peripheral membrane forms that interacts with holo-CRBP (type I). Biochemistry 34: 7027–7037

    Article  PubMed  CAS  Google Scholar 

  6. Herr F, Ong DE (1992) Differential interaction of lecithln:retinol acyltransfersase with cellular retinoid-binding proteins. Biochemistry 31: 6748–6755

    Article  PubMed  CAS  Google Scholar 

  7. Ottonello S, Petrucco S, Maraini G (1987) Vitamin A uptake from retinol-binding protein in a cell-free system from pigment epithelial cells of bovine retina: retinol transfer from plasma retinol-binding protein to cytoplasmic retinol-binding protein with retinyl-ester formation as the intermediate step. J Biol Chem 262: 3975–3981

    PubMed  CAS  Google Scholar 

  8. Boerman MHEM, Napoli JL (1991) Cholate-independent retinyl ester hydrolysis: stimulation by apo-cellular retinol binding protein. J Biol Chem 266: 22273–22278

    PubMed  CAS  Google Scholar 

  9. Napoli JL, Pacia EB, Salerno GJ (1989) Cholate-independent hydrolysis of all-trans-retinyl palmitate by rat tissues: solubilization of multiple kidney microsomal hydrolases. Arch Biochem Biophys 274: 192–199

    Article  PubMed  CAS  Google Scholar 

  10. Harrison EH, Gad M (1989) Hydrolysis of retinyl palmitate by enzymes of rat pancreas and liver: differentiation of bile salt-dependent and bile salt-independent, neutral retinyl ester hydrolases in rat liver. J Biol Chem 264: 17142–17147

    PubMed  CAS  Google Scholar 

  11. Gad MZ, Harrison EH (1991) Neutral and acid retinyl ester hydrolases associated with rat liver microsomes: relationships to microsomal cholesteryl ester hydrolases. J Lipid Res 32: 685–694

    PubMed  CAS  Google Scholar 

  12. Sun G, Alexon SEH, Harrison EH (1997) Purification and characterization of a neutral, bile salt-independent retinyl ester hydrolase from rat liver microsomes: relationship to rat carboxylesterase ES-2. J Biol Chem 272: 24488–24493

    Article  PubMed  CAS  Google Scholar 

  13. Posch KC, Boerman MHEM, Burns RD, Napoli JL (1991) Holo-cellular retinol binding protein as a substrate for microsomal retinal synthesis. Biochemistry 30: 6224–6230

    Article  PubMed  CAS  Google Scholar 

  14. Ottonello S, Scita G, Mantovani G, Cavazzini D, Rossi GL (1993) Retinol bound to cellular retinol binding-protein is a substrate for cytosolic retinoic acid synthesis. J Biol Chem 268: 27133–27142

    PubMed  CAS  Google Scholar 

  15. Boerman MHEM, Napoli JL (1996) Cellular retinol-binding protein-supported retinoic acid synthesis: relative roles of microsomes and cytosol. J Biol Chem 271: 5610–5616

    Article  PubMed  CAS  Google Scholar 

  16. Posch KC, Bums RD, Napoli JL (1992) Biosynthesis of all-trans-retinoic acid from retinal: recognition of retinal bound to cellular retinol binding protein (type I) as substrate by a purified cytosolic dehydrogenase. J Biol Chem 267: 19676–19682

    PubMed  CAS  Google Scholar 

  17. Wang X, Penzes P, Napoli JL (1996) Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli: recognition of retinal as substrate and role in retinoic acid synthesis. J Biol Chem 271: 16288–16293

    Article  PubMed  CAS  Google Scholar 

  18. Penzes P, Wang X, Napoli JL (1997) Enzymatic characteristics of retinal dehydrogenase type I expressed in Escherichia coll. Biochim Biophys Acta 1342: 175–181

    Article  CAS  Google Scholar 

  19. Napoli JL (1986) Retinol metabolism in LLC-PK1 cells: characterization of retinoic acid synthesis by an established mammalian cell line. J Biol Chem 261: 13592–13597

    PubMed  CAS  Google Scholar 

  20. Sigenthaler G, Saurat J-H, Ponec M (1990) Retinol and retinoic acid metabolism: relationship to the state of differentiation of cultured human keratinocytes. Biochem J 268: 371–378

    Google Scholar 

  21. Randolph RK, Simon M (1993) Characterization of retinol metabolism in cultured human epidermal keratinocytes. J Biol Chem 268: 9198–9205

    PubMed  CAS  Google Scholar 

  22. Haq RU, Chytil F (1988) Retinoic acid rapidly induces lung cellular retinol-binding protein mRNA levels in retinol deficient rats. Biochem Biophys Res Commun 156: 712–716

    Article  PubMed  CAS  Google Scholar 

  23. Matsuura T, Ross AC (1993) Regulation of hepatic lecithln:retinol acyltransferase activity by retinoic acid. Arch Biochem Biophys 301: 221–227

    Article  PubMed  CAS  Google Scholar 

  24. Penzes P, Wang X, Napoli JL (1997) Cloning of a cDNA encoding retinal dehydrogenase isozyme type and its expression in Escherichia coli. Gene 191: 167–172

    CAS  Google Scholar 

  25. Williams JB, Napoli JL (1985) Metabolism of retinoic acid and retinol during differentiation of F9 embryonal carcinoma cells. Proc Natl Acad Sci. USA 82: 4658–4662

    Article  PubMed  CAS  Google Scholar 

  26. Kurlandsky SB, Duell EA, Kang S, Voorhees JJ, Fisher GJ (1996) Autoregulation of retinoic acid biosynthe-sis through regulation of retinol esterification in human keratinocytes. J Biol Chem 271: 15346–15352

    Article  PubMed  CAS  Google Scholar 

  27. Sigenthaler G, Saurat J-H, Ponec M (1990) Retinol and retinoic acid metabolism: relationship to the state of differentiation of cultured human keratinocytes. Biochem J 268: 371–378

    Google Scholar 

  28. Randolph RK, Simon M (1993) Characterization of retinol metabolism in cultured human epidermal keratinocytes. J Biol Chem 268: 9198–9205

    PubMed  CAS  Google Scholar 

  29. Shingleton JL, Skinner MK, Ong DE (1989) Characteristics of retinol accumulated from serum retinol-binding protein by cultured Sertoli cells. Biochemistry 28: 9641–9647

    Article  PubMed  CAS  Google Scholar 

  30. Bishop PD, Griswald MD (1987) Uptake and metabolism of retinol in cultured Sertoli cells: evidence for a kinetic model. Biochemistry 26: 7511–7518

    Article  PubMed  CAS  Google Scholar 

  31. van Wauwe JP, Coene M-C, Goossens J, van Nyen J, Cools W, Lauwers W (1988) Ketoconazole inhibits the in vivo and in vitro metabolism of all-trans-retinoic acid. J Pharmacol Exp Ther 245: 718–722

    PubMed  Google Scholar 

  32. van Wauwe JP, Coene MC, Goossens J, Cools W, Monbaliu J (1990) Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in the rats. J Pharmacol Exp Ther 252: 365–369

    PubMed  Google Scholar 

  33. van der Leede BM, van den Brink CE, Pijnappel WWM, Sonneveld E, van der Saag PT, van der Burg B (1997) Autoinduction of retinoic acid metabolism to polar derivatives with decreased biological activity in retinoic acid-sensitive, but not in retinoic acid-resistant human breast cancer cells. J Biol Chem 272: 17921–17928

    Article  PubMed  Google Scholar 

  34. Pijnappel WWM, Hendricks HFJ, Folkers GE, van den Brink CE, Dekker EJ, Edelenbosch C, van der Saag PJ, Durston AJ (1993) The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366: 340–344

    Article  PubMed  CAS  Google Scholar 

  35. Fiorella PD, Napoli JL (1991) Expression of cellular retinoic acid binding protein in Escherichia coli: characterization and evidence that holo-CRABP is a substrate in retinoic acid metabolism. J Biol Chem 266: 16572–16579

    PubMed  CAS  Google Scholar 

  36. Fiorella PD, Napoli JL (1994) Microsomal retinoic acid metabolism: effects of cellular retinoic acid-binding protein (type I) and C18-hydroxylation as an initial step. J Biol Chem 269: 10538–10544

    PubMed  CAS  Google Scholar 

  37. Penzes P, Napoli JL (1999) Holo-cellular retinol-binding protein: distinction of ligand-binding affinity from efficiency as substrate in retinal biosynthesis. Biochemistry 38: 2088–2093

    Article  PubMed  CAS  Google Scholar 

  38. Chai X, Boerman MHEM, Zhai Y, Napoli JL 1995) Cloning of a cDNA for liver microsomal retinol dehydrogenase: a tissue-specific, short-chain alcohol dehydrogenase. J Biol Chem 270: 3900–3904

    Article  PubMed  CAS  Google Scholar 

  39. Chai X, Zhai Y, Popescu G, Napoli JL (1995) Cloning of a cDNA for a second retinol dehydrogenase, type II: expression of its mRNA relative to type I. J Biol Chem 270: 28408–28412

    Article  PubMed  CAS  Google Scholar 

  40. Chai X, Zhai Y, Napoli JL (1996) Cloning of a cDNA encoding a retinol dehydrogenase isozyme type III. Gene 169: 219–222

    Article  PubMed  CAS  Google Scholar 

  41. Romert A, Tuvendal P, Simon A, Dencker L, Eriksson U (1998) The identification of a 9-cis-retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. Proc Natl Acad Sci. USA 95: 4404–4409

    Article  PubMed  CAS  Google Scholar 

  42. Simon A, Hellman U, Wernstedt C, Eriksson U (1995) The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. J Biol Chem 270: 1107–1112

    Article  PubMed  CAS  Google Scholar 

  43. Simon A, Lagercrantz J, Bajalica-Lagercrantz S, Eriksson U (1996) Primary structure of human 11-cis retinol dehydrogenase and organization and chromosomal localization of the corresponding gene. Genomics 36: 424–430

    Article  PubMed  CAS  Google Scholar 

  44. Driessen CAGG, Janssen BPM, Winkens HJ, v In Vugt AHM, de Leeuw TLM, Janssen JJM (1995) Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Invest. Ophthalmol. Vis. Sci. 36: 1988–1996

    Google Scholar 

  45. Mertz JR, Shang E, Pianedosi R, Wei S, Wolgemuth DJ, Blaner WS (1997) Identification and characterization of a stereospecific human enzyme that catalyzes 9-cis-retinol oxidation: a possible role in 9-cis-retinoic acid formation. J Biol Chem 272: 11744–11749

    Article  PubMed  CAS  Google Scholar 

  46. Chai X, Zhai Y, Napoli JL (1997) cDNA cloning and characterization of a cis-retinoll3cs-hydroxysterol short-chain dehydrogenase. J Biol Chem 272: 33125–33131

    Article  PubMed  CAS  Google Scholar 

  47. Su J, Chai X, Kahn B, Napoli JL (1998) cDNA cloning, tissue distribution, and substrate characterization of a cis-retinol/3a-hydroxysterol short-chain dehydrogenase isozyme. J Biol Chem 273: 17910–17916

    Article  PubMed  CAS  Google Scholar 

  48. Biswas MG, Russell DW (1997) Expression cloning and characterization of oxidative 173- and 3a-hydroxysteroid dehydrogenases from rat and human prostate. J Biol Chem 272: 15959–15966

    Article  PubMed  CAS  Google Scholar 

  49. Haeseleer F, Huang J, Lebioda L, Saari JC, Palczewski K (1998) Molecular characterization of a novel short-chain dehydrogenase/reductase. J Biol Chem 273: 21790–21799

    Article  PubMed  CAS  Google Scholar 

  50. Gough WH, VanOoteghem S, Sint T, Kedishvili NY (1998) cDNA cloning and characterization of a new human microsomal NADtdependent dehydrogenase that oxidizes all-trans-retinol and 3a-hydroxysteroids. J Biol Chem 273: 19778–19785

    Article  PubMed  CAS  Google Scholar 

  51. Wang J, Chai X, Eriksson U, Napoli JL (1999) Activity of human RdhS with steroids and retinoids and expression of its mRNA in extra-ocular human tissue. Biochem J 338: 23–27

    Article  PubMed  CAS  Google Scholar 

  52. Zhai Y, Higgins D, Napoli JL (1997) Coexpression of the mRNAs encoding retinol dehydrogenase isozymes and cellular retinol-binding protein. J Cell Physiol 173: 36–43

    Article  PubMed  CAS  Google Scholar 

  53. Båvik CO, Ward SJ, Ong DE (1997) Identification of a mechanism to localize generation of retinoic acid in rat embryos. Mech Develop 69: 155–167

    Article  Google Scholar 

  54. Young CY, Murtha PE, Andrews PE, Lindzey JK, Tindall DJ (1994) Antagonism of androgen action in prostate tumor cells by retinoic acid. Prostate 25: 39–45

    Article  PubMed  CAS  Google Scholar 

  55. De Coster R, Wouters W, Bruynseels J (1996) P450-dependent enzymes as targets for prostate cancer therapy. J Steroid Biochem Mol Biol 56: 133–143

    Article  PubMed  Google Scholar 

  56. Boudou P, Chivot M, Vexiau P, Soliman H, Villette JM, Belanger A, Fiet J (1994) Evidence for decreased androgen 5a-reductase in skin and liver of men with severe acne after 13-cis-retinoic acid treatment. J Clin Endocrinol Metab 78: 1064–1069

    Article  PubMed  CAS  Google Scholar 

  57. Boudou P, Soliman H, Chivot M, Villette JM, Vexiau P, Belanger A, Fiet J (1995) Effect of oral isotretinoin treatment on skin androgen receptor levels in male acneic patients. J Clin Endocrinol Metab 80: 1158–1161

    Article  PubMed  CAS  Google Scholar 

  58. Huang HF, Li MT, Von Hagen S, Zhang YE Irwin RJ (1997) Androgen modulation of the messenger ribonucleic acid of retinoic acid receptors in the prostate seminal vesicles and kidney in the rat. Endocrinology 138: 553–559

    Article  PubMed  CAS  Google Scholar 

  59. Russell DW, Wilson JD (1994) Steroid 5a-reductase: two genes/two enzymes. Annu Rev Biochem 63: 25–61

    Article  PubMed  CAS  Google Scholar 

  60. Taurog JD, Moore RJ, Wilson JD (1975) Partial characterization of the cytosol 3a-hydroxysteroid:NAD(P)* oxidoreductase of rat ventral prostate. Biochemistry 14: 810–817

    Article  PubMed  CAS  Google Scholar 

  61. Lin H-K, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM (1997) Expression and characterization of recombinant type 2 3a-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3a/17ß-HSD activity and cellular distribution. Mol Endocrinol 11: 1971–1984

    Article  PubMed  CAS  Google Scholar 

  62. Bruchovsky N (1971) Comparison of the metabolites formed in rat prostate following the in vivo administration of seven natural androgens. Endocrinology 89: 1212–1222

    Article  PubMed  CAS  Google Scholar 

  63. Moore RJ, Wilson JD (1993) The effect of androgenic homones on the reduced nicotinamide adenine dinucleotide phosphate 5–4–3-ketosteroid-5a-oxidoreductase of rat ventral prostate. Endocrinology 93: 581–592

    Article  Google Scholar 

  64. Schultz FM, Wilson JD (1974) Virulization of the Wolffian duct in the rat fetus by various androgens. Endocrinology 94: 979–986

    Article  PubMed  CAS  Google Scholar 

  65. Mahendroo MS, Cala KM, Russell DW (1996) 5a-Reduced androgens play a key role in murine parturition. Mol Endocrinol 10: 380–392

    Article  PubMed  CAS  Google Scholar 

  66. Lee MO, Manthey CL, Sladek NE (1991) Identification of mouse liver aldehyde dehydrogenases that catalyze the oxidation of retinaldehyde to retinoic acid. Biochem Pharmacol 42: 1279–1285

    Article  PubMed  CAS  Google Scholar 

  67. Dockham PA, Le e MO, Sladek NE (1992) Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde. Biochem Pharmacol 43: 2453–2469

    Google Scholar 

  68. Bhat PV, Labrecque J, Boutin JM, Lacroix A, oshida A (1995) Cloning of a cDNA encoding rat aldehyde dehydrogenase with high activity for retinal oxidation. Gene 166: 303–306

    Article  PubMed  CAS  Google Scholar 

  69. Zhao D, McCaffery P, Ivins KJ, Neve RL, Hogan P, Dräger U (1996) Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur J Biochem 240: 5–22

    Article  Google Scholar 

  70. Saari JC, Champer RI, Asson-Batres M, Garwin GG, Huang J, Crabb JW, Milam AH (1995) Characterization and localization of an aldehyde dehydrogenase to amacrine cells of bovine retina. Visual Neurosci 12: 263–272

    Article  CAS  Google Scholar 

  71. Godbout R, Packer M, Poppema S, Dabragh L (1996) Localization of cytosolic aldehyde dehydrogenase in the developing chick retina: in situ hybridization and immunochemical analyses. Develop Dyn 205: 319–331

    Article  CAS  Google Scholar 

  72. El Akawi Z, Napoli JL (1994) Rat liver cytosolic retinal dehydrogenase: comparison of 13-cis-9-cis-, and alltrans-retinal as substrates and effects of cellular retinoid-binding proteins and retinoic acid on activity. Biochemistry 33: 1938–1943

    Article  PubMed  CAS  Google Scholar 

  73. Labrecque J, Dumas F, Lacroix A, Bhat PV (1995) A novel isoenzyme of aldehyde dehydrogenase specifically involved in the biosynthesis of 9-cis and all-trans retinoic acid. Biochem J 305: 681–684

    PubMed  CAS  Google Scholar 

  74. Nagao A, Olson JA (1994) Enzymatic formation of 9-cis, 13-cis, and all-trans-retinals from isomers of 1-carotene. FASEB J 8: 968–973

    PubMed  CAS  Google Scholar 

  75. Lamb AL, Wang X, Napoli JL, Newcomer ME (1998) Purification, crystallization and preliminary X-ray diffraction studies of retinal dehydrogenase type II. Acta Crystallogr 54: 639–642

    CAS  Google Scholar 

  76. Lamb A, Newcomer M (1999) The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity. Biochemistry 38; in press

    Google Scholar 

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Napoli, J.L. (2000). Enzymology and biogenesis of retinoic acid. In: Livrea, M.A. (eds) Vitamin A and Retinoids: An Update of Biological Aspects and Clinical Applications. MCBU Molecular and Cell Biology Updates. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8454-9_2

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  • DOI: https://doi.org/10.1007/978-3-0348-8454-9_2

  • Publisher Name: Birkhäuser, Basel

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