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Molecular and Cellular Biochemistry

, Volume 4, Issue 2, pp 79–95 | Cite as

Hydroxylations in biosynthesis and metabolism of bile acids

  • Ingemar Björkhem
  • Henry Danielsson
Review and General Articles a. review articles

Summary

Recent development in research concerning hydroxylations in biosynthesis and metabolism of bile acids is reviewed. In the conversion of cholesterol into bile acids, hydroxyl groups may be introduced into the following positions: C-6α, C-6β, C-7α, C-12α, C-16α, C-23, C-24, C-25, and C-26. With the exception of the 26-hydroxylation and probably the 24-hydroxylation, which are also catalyzed by the mitochondrial fraction, the different hydroxylations are catalyzed by the microsomal fraction of liver homogenate and require NADPH and molecular oxygen. With the possible exception of the 12α-hydroxylase, all the microsomal hydroxylations appear to involve participation of cytochrome P-450 and NADPH-cytochrome P-450 reductase. Several of the hydroxylations have been demonstrated in reconstituted systems consisting of partially purified cytochrome P-450, NADPH-cytochrome P-450 reductase and a phospholipid. The specificity of the hydroxylation is determined mainly by the cytochrome P-450 fraction. The cholesterol 7α-hydroxylase catalyzes the major rate-limiting step in the overall conversion of cholesterol into bile acids. The combined activities of the microsomal 26-hydroxylase and the 12α-hydroxylase play a major role in determining the ratio between cholic acid and chenodeoxycholic acid formed from cholesterol. There is a close relationship between the cholesterol 7α-hydroxylase activity and the rate of cholesterol biosynthesis. The regulatory role of the cholesterol 7α-hydroxylase, the 12α-hydroxylase and the microsomal 26-hydroxylase may be correlated with some specific properties of the enzyme systems which differ markedly from the properties of the other hydroxylases involved in biosynthesis and metabolism of bile acids. The influence of different factors on the hydroxylations has been studied and the physiological implications of the different effects are discussed.

Keywords

Cholesterol NADPH Bile Acid Molecular Oxygen Cholic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    H. Danielsson and T. T. Tchen, in Metabolic Pathways (D. M., Greenberg, editor) Vol. II, pp. 117–168, Academic Press, New York (1968).Google Scholar
  2. 2.
    H. Danielsson and K. Einarsson, in The Biological Basis of Medicine (E. E. Bittar, and N. Bittar, editors) Vol. V, pp. 279–315, Academic Press, London. (1969).Google Scholar
  3. 3.
    W. H. Elliott and P. M. Hyde, Amer. J. Med. 51, 568–579 (1971).PubMedGoogle Scholar
  4. 4.
    H. Danielsson, in The Bile Acids: Chemistry, Physiology and Metabolism (P. P. Nair, and D. Kritchevsky, editors) Vol. II, pp. 1–32 and 305–306, Plenum Press, New York (1973).Google Scholar
  5. 5.
    A. Y. H. Lu, R. Kuntzman, S. West, M. Jacobson and A. H. Conney, J. Biol. Chem. 247, 1727–1734 (1972).PubMedGoogle Scholar
  6. 6.
    H. Danielsson and K. Einarsson, J. Biol. Chem. 142, 1449–1454 (1966).Google Scholar
  7. 7.
    I. Björkhem and J. Gustafsson, Eur. J. Biochem. 36, 201–212 (1973).PubMedGoogle Scholar
  8. 8.
    T. Cronholm and G. Johansson, Eur. J. Biochem. 16, 373–381 (1970).PubMedGoogle Scholar
  9. 9.
    O. Berséus, H. Danielsson and K. Einarsson, J. Biol. Chem. 242, 1211–1219 (1967).PubMedGoogle Scholar
  10. 10.
    O. Berséus, H. Danielsson and A. Kallner, J. Biol. Chem. 240, 2396–2401 (1965).PubMedGoogle Scholar
  11. 11.
    I. Björkhem, H. Danielsson, C. Issidorides and A. Kallner, Acta Chem. Scand. 19, 2151–2154 (1965).PubMedGoogle Scholar
  12. 12.
    I. Björkhem, Eur. J. Biochem. 8, 337–344 (1969).PubMedGoogle Scholar
  13. 13.
    I. Björkhem, Eur. J. Biochem. 18, 299–304 (1971).PubMedGoogle Scholar
  14. 14.
    I. Björkhem, Eur. J. Biochem. 27, 354–363 (1972).PubMedGoogle Scholar
  15. 15.
    I. Björkhem, to be published (1974).Google Scholar
  16. 16.
    M. X. Zarrow, J. M. Yochim and J. L. McCarthy, Experimental Endocrinology, pp. 240–242, Academic Press, New York (1964).Google Scholar
  17. 17.
    S. Bergström and U. Gloor, Acta Chem. Scand. 9, 34–38 (1955).Google Scholar
  18. 18.
    G. L. Sottocasa, B. Kuylenstierna, L. Ernster and A. Bergstrand, in Methods of Enzymology (S. P. Colowick, N. O. Kaplan, R. W. Estabrook, and M. E. Pullman, editors) Vol. X, pp. 448–463, Academic Press, New York (1967).Google Scholar
  19. 19.
    G. F. Wilgram and E. P. Kennedy, J. Biol. Chem. 238, 2615–2619 (1963).PubMedGoogle Scholar
  20. 20.
    E. L. Kuff and W. C. Schneider, J. Biol. Chem. 206, 677–685 (1954).PubMedGoogle Scholar
  21. 21.
    O. H. Lowry, N. J. Rosebrough, A. L. Farr and R. J. Randall, J. Biol. Chem. 193, 265–275 (1951).PubMedGoogle Scholar
  22. 22.
    H. K. Hanel and H. Dam, Acta Chem. Scand. 9, 677–682 (1955).Google Scholar
  23. 23.
    T. Omura and R. Sato, J. Biol. Chem. 239, 2379–2385 (1964).PubMedGoogle Scholar
  24. 24.
    B. S. S. Masters, C. H. Williams, Jr. and H. Kamin, in Methods of Enzymology (S. P. Colowick, N. O. Kaplan, R. W. Estabrook, and M. E. Pullman, edtors) Vol. X, pp 565–573, Academic Press, New York (1967).Google Scholar
  25. 25.
    P. Eneroth, J. Lipid Res. 4, 11–16 (1963).Google Scholar
  26. 26.
    R. W. Estabrook, A. G. Hildebrandt, J. Baron, K. J. Netter and K. Leibman, Biochem. Biophys. Res. Commun. 42, 132–139 (1971).PubMedGoogle Scholar
  27. 27.
    A. G. Hildebrandt and R. W. Estabrook, Arch. Biochem. Biophys. 143, 66–79 (1971).PubMedGoogle Scholar
  28. 28.
    I. Björkhem and H. Danielsson, Biochem. Biophys. Res. Commun. 51, 766–774 (1973).PubMedGoogle Scholar
  29. 29.
    J. R. Gillette, Metabolism 20, 215 (1971).PubMedGoogle Scholar
  30. 30.
    J. R. Mitton, N. A. Scholan and G. S. Boyd, Eur. J. Biochem. 20, 569–579 (1971).PubMedGoogle Scholar
  31. 31.
    G. Johansson, Eur. J. Biochem. 21, 68–79 (1971).PubMedGoogle Scholar
  32. 32.
    S. Shefer, S. Hauser and E. H. Mosbach, J. Lipid Res. 9, 328–333 (1968).PubMedGoogle Scholar
  33. 33.
    S. Balasubramaniam, K. A. Mitropoulos and N. B. Myant, Eur. J. Biochem. 34, 77–83 (1973).PubMedGoogle Scholar
  34. 34.
    I. Björkhem and H. Danielsson, Anal. Biochem. in press (1974).Google Scholar
  35. 35.
    K. A. Mitropoulos and S. Balasubramaniam, Biochem. J. 128, 1–9 (1972).PubMedGoogle Scholar
  36. 36.
    G. S. Boyd, A. M. Grimwade and M. E. Lawson, Eur. J. Biochem. 37, 334–340 (1973).PubMedGoogle Scholar
  37. 37.
    F. Wada, K. Hirata, K. Nakano and Y. Sakamoto, J. Biochem. 66, 699–703 (1969).PubMedGoogle Scholar
  38. 38.
    K. Einarsson and G. Johansson, Eur. J. Biochem. 6, 293–298 (1968).PubMedGoogle Scholar
  39. 39.
    S. Shefer, S. Hauser and E. H. Mosbach, J. Lipid Res. 13, 69–70 (1972).PubMedGoogle Scholar
  40. 40.
    H. Danielsson, K. Einarsson and G. Johansson, Eur. J. Biochem. 2, 44–49 (1967).PubMedGoogle Scholar
  41. 41.
    G. Johansson, Eur. J. Biochem. 17, 292–295 (1970).PubMedGoogle Scholar
  42. 42.
    Y. Imay and R. Sato, Eur. J. Biochem. 1, 419–426 (1967).PubMedGoogle Scholar
  43. 43.
    K. Einarsson, Eur. J. Biochem. 5, 101–108 (1968).PubMedGoogle Scholar
  44. 44.
    M. Suzuki, K. A. Mitropoulos and N. B. Myant, Biochem. Biophys. Res. Commun. 30, 516–521 (1968).PubMedGoogle Scholar
  45. 45.
    C. Bernhardsson, I. Björkhem, H. Danielsson and K. Wikvall, Biochem. Biophys. Res. Commun. 54, 1030–1038 (1973).PubMedGoogle Scholar
  46. 46.
    K. A. Mitropoulos, M. Suzuki, N. B. Myant and H. Danielsson, FEBS Letters, 1, 13–15 (1968).PubMedGoogle Scholar
  47. 47.
    I. Björkhem, J. Gustafsson and G. Johansson, to be published (1974).Google Scholar
  48. 48.
    I. Björkhem, H. Danielsson and K. Wikvall, to be published (1974).Google Scholar
  49. 49.
    I. Björkhem, H. Danielsson and J. Gustafsson, FEBS Letters 31, 20–22 (1973).PubMedGoogle Scholar
  50. 50.
    I. Björkhem and J. Gustafsson, J. Biol. Chem. in press. (1974).Google Scholar
  51. 51.
    K. Okuda and N. Hoshita, Biochim. Biophys. Acta 164, 381–388 (1968).PubMedGoogle Scholar
  52. 52.
    T. Masui and E. Staple, J. Biol. Chem. 241, 3889–3893 (1966).PubMedGoogle Scholar
  53. 53.
    K. Einarsson and G. Johansson, FEBS Letters 4, 177–180 (1969).PubMedGoogle Scholar
  54. 54.
    D. Trülzsch, H. Greim, P. Czygan, F. Hutterer, F. Schaffner, H. Popper, D. Y. Cooper and O. Rosenthal, Biochemistry 12, 76–79 (1973).PubMedGoogle Scholar
  55. 55.
    I. Björkhem, H. Danielsson and K. Wikvall, Biochem. Biophys. Res. Commun. 53, 609–616 (1973).PubMedGoogle Scholar
  56. 56.
    H. W. Strobel, A. Y. H. Lu, J. Heidema and M. J. Coon, J. Biol. Chem. 245, 4851–4854 (1970).PubMedGoogle Scholar
  57. 57.
    I. Björkhem, H. Danielsson and K. Wikvall, J. Biol. Chem. (1974).Google Scholar
  58. 58.
    W. Voigt, S. L. Hsia, D. Y. Cooper and O. Rosenthal, FEBS Letters 2, 124–126 (1968).PubMedGoogle Scholar
  59. 59.
    H. Danielsson, Steroids 22, 567–579 (1973).PubMedGoogle Scholar
  60. 60.
    S. Bergström and H. Danielsson, Acta Physiol. Scand. 43, 1–7 (1958).Google Scholar
  61. 61.
    S. Shefer, S. Hauser, I. Bekersky and E. H. Mosbach, J. Lipid Res. 10, 646–655 (1969).PubMedGoogle Scholar
  62. 62.
    S. Shefer, S. Hauser, I. Bekersky and E. H. Mosbach, J. Lipid Res. 11, 404–411 (1970).PubMedGoogle Scholar
  63. 63.
    N. B. Myant and H. A. Eder, J. Lipid Res. 2, 363–368. (1961).Google Scholar
  64. 64.
    H. J. Weis and J. M. Dietschy, J. Clin. Invest. 48, 2398–2408 (1969).PubMedGoogle Scholar
  65. 65.
    P. Back, B. Hamprecht and F. Lynen, Arch. Biochem. Biophys. 133, 11–21 (1969).PubMedGoogle Scholar
  66. 66.
    B. Hamprecht, C. Nüssler, G. Waltinger and F. Lynen, Eur. J. Biochem. 18, 10–14 (1971).PubMedGoogle Scholar
  67. 67.
    B. Hamprecht, R. Roscher, G. Waltinger and C. Nussler, Eur. J. Biochem. 18, 15–19 (1971).PubMedGoogle Scholar
  68. 68.
    H. Danielsson, Steroids 20, 63–72 (1972).PubMedGoogle Scholar
  69. 69.
    A. A. Kandutsch and S. E. Saucier, J. Biol. Chem. 244, 2299–2305 (1969).PubMedGoogle Scholar
  70. 70.
    J. Gielen, J. van Cantfort, B. Robaye and J. Renson, C.R. Acad. Sci, 269, 731–732 (1969).Google Scholar
  71. 71.
    J. Gielen, B. Robaye, J. van Cantfort and J. Renson, Arch. Int. Pharmacodyn. 183, 403–405 (1970).PubMedGoogle Scholar
  72. 72.
    D. Mayer and A. Voges, Hoppe-Seyler's Z. Physiol. Chem. 353, 1187–1188 (1972).PubMedGoogle Scholar
  73. 73.
    K. A. Mitropoulos, S. Balasubramaniam, G. F. Gibbons and B. E. A. Reeves, FEBS Letters, 27, 203–206 (1972).PubMedGoogle Scholar
  74. 74.
    K. Einarsson and G. Johansson, FEBS Letters 1, 219–222 (1968).PubMedGoogle Scholar
  75. 75.
    H. Danielsson, Steroids 22, 667–676 (1973).PubMedGoogle Scholar
  76. 76.
    S. Shefer, S. Hauser, V. Lapar and E. H. Mosbach, J. Lipid Res. 14, 573–580 (1973).PubMedGoogle Scholar
  77. 77.
    E. H. Mosbach, Arch. Intern. Med. 130, 478–487 (1972).PubMedGoogle Scholar

Copyright information

© Dr. W. Junk b.v. Publishers 1974

Authors and Affiliations

  • Ingemar Björkhem
    • 1
  • Henry Danielsson
    • 1
  1. 1.Department of ChemistryKarolinska InstitutetStockholmSweden

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