Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1980 Jun;65(6):1418–1430. doi: 10.1172/JCI109806

Cerebrotendinous xanthomatosis: a defect in mitochondrial 26-hydroxylation required for normal biosynthesis of cholic acid.

H Oftebro, I Björkhem, S Skrede, A Schreiner, J I Pederson
PMCID: PMC371480  PMID: 7410549

Abstract

Oxidation of side chain of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was studied in a patient with cerebrotendinous xanthomatosis (CTX) and in control subjects, using various subcellular fractions of liver homogenate and a method based on isotope dilution-mass spectrometry. In the control, 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was converted into 5 beta-cholestane-3 alpha,7 alpha,12 alpha,26-tetrol and 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid by the mitochondrial fraction, and into 5 beta-cholestane-3 alpha,7 alpha,12 alpha,-25-tetrol by the microsomal fraction. In the CTX patient, liver mitochondria were completely devoid of 26-hydroxylase activity. The same mitochondrial fraction catalyzed 25-hydroxylation of vitamin D3. The microsomal fraction of liver of the subject with CTX contained more than 50-fold the normal amount of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol. The basic metabolid defect in CTX appears to be a lack of the mitochondrial 26-hydroxylase. The excretion in the bile of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 alpha,25-pentol observed in CTX patients may be secondary to the accumulation of the major substrate for the 26-hydroxylase, i. e., 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, and exposure of this substrate to the normally less active microsomal 25-and 24-hydroxylases. It is concluded that the major pathway in the biosynthesis of cholic acid in human liver involves a mitochondrial C27-steroid 26-hydroxylation.

Full text

PDF
1418

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arvidson G. A. Structural and metabolic heterogeneity of rat liver glycerophosphatides. Eur J Biochem. 1968 May;4(4):478–486. doi: 10.1111/j.1432-1033.1968.tb00237.x. [DOI] [PubMed] [Google Scholar]
  2. BERSEUS O., DANIELSSON H., KALLNER A. SYNTHESIS AND METABOLISM OF CHOLEST-4-ENE-7-ALPHA,12-ALPHA-DIOL-3-ONE AND 5-BETA-CHOLESTANE-7-ALPHA,12-ALPHA-DIOL-3-ONE. BILE ACIDS AND STEROIDS 153. J Biol Chem. 1965 Jun;240:2396–2401. [PubMed] [Google Scholar]
  3. BERSEUS O. ON THE STEREOSPECIFICITY OF 26-HYDROXYLATION OF CHOLESTEROL. BILE ACIDS AND STEROIDS. 155. Acta Chem Scand. 1965;19:325–328. [PubMed] [Google Scholar]
  4. BRIDGWATER R. J. Partial synthesis of the two 3alpha:7alpha:12alpha-trihydroxycoprostanic acids and of similar bile acids with extended chains. Biochem J. 1956 Dec;64(4):593–599. doi: 10.1042/bj0640593a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bjorkhem I., Holmberg I. A novel specific assay of 25-hydroxy vitamin D. Clin Chim Acta. 1976 May 3;68(3):215–221. doi: 10.1016/0009-8981(76)90384-3. [DOI] [PubMed] [Google Scholar]
  6. Björkheim I., Danielsson H., Einarsson K., Johansson G. Formation of bile acids in man: conversion of cholesterol into 5-beta-cholestane-3-alpha, 7-alpha, 12-alpha-triol in liver homogenates. J Clin Invest. 1968 Jul;47(7):1573–1582. doi: 10.1172/JCI105849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Björkhem I., Danielsson H. Biosynthesis and metabolism of bile acids in man. Prog Liver Dis. 1976;5:215–231. [PubMed] [Google Scholar]
  8. Björkhem I., Gustafsson J., Johansson G., Persson B. Biosynthesis of bile acids in man. Hydroxylation of the C27-steroid side chain. J Clin Invest. 1975 Mar;55(3):478–486. doi: 10.1172/JCI107954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Björkhem I., Gustafsson J. Omega-hydroxylation of steriod side-chain in biosynthesis of bile acids. Eur J Biochem. 1973 Jul 2;36(1):201–212. doi: 10.1111/j.1432-1033.1973.tb02902.x. [DOI] [PubMed] [Google Scholar]
  10. Björkhem I., Holmberg I. Assay and properties of a mitochondrial 25-hydroxylase active on vitamine D3. J Biol Chem. 1978 Feb 10;253(3):842–849. [PubMed] [Google Scholar]
  11. Björkhem I., Holmberg I. On the 25-hydroxylation of vitamin D3 in vitro studied with a mass fragmentographic technique. J Biol Chem. 1979 Oct 10;254(19):9518–9524. [PubMed] [Google Scholar]
  12. Björkhem I. Selective ion monitoring in clinical chemistry. CRC Crit Rev Clin Lab Sci. 1979 Aug;11(1):53–105. doi: 10.3109/10408367909105854. [DOI] [PubMed] [Google Scholar]
  13. CAREY J. B., Jr CONVERSION OF CHOLESTEROL TO TRIHYDROXYCOPROSTANIC ACID AND CHOLIC ACID IN MAN. J Clin Invest. 1964 Jul;43:1443–1448. doi: 10.1172/JCI105020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. CAREY J. B., Jr, HASLEWOOD G. A. Crystallization of trihydroxycoprostani acid from human bile. J Biol Chem. 1963 Feb;238:855–856. [PubMed] [Google Scholar]
  15. CLELAND W. W. Computer programmes for processing enzyme kinetic data. Nature. 1963 May 4;198:463–465. doi: 10.1038/198463a0. [DOI] [PubMed] [Google Scholar]
  16. Cronholm T., Johansson G. Oxidation of 5 beta-cholestane-3alpha, 7alpha, 12alpha-triol by rat liver microsomes. Eur J Biochem. 1970 Oct;16(2):373–381. doi: 10.1111/j.1432-1033.1970.tb01091.x. [DOI] [PubMed] [Google Scholar]
  17. Danielsson H., Sjövall J. Bile acid metabolism. Annu Rev Biochem. 1975;44:233–253. doi: 10.1146/annurev.bi.44.070175.001313. [DOI] [PubMed] [Google Scholar]
  18. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  19. Gustafsson J., Sjöstedt S. On the stereospecificity of microsomal "26"-hydroxylation in bile acid biosynthesis. J Biol Chem. 1978 Jan 10;253(1):199–201. [PubMed] [Google Scholar]
  20. HASLEWOOD G. A. D. Comparative studies of bile salts. V. Bile salts of Crocodylidae. Biochem J. 1952 Dec;52(4):583–587. doi: 10.1042/bj0520583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hanson R. F., Staples A. B., Williams G. C. Metabolism of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol into cholic acid in normal human subjects. J Lipid Res. 1979 May;20(4):489–493. [PubMed] [Google Scholar]
  22. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  23. Pedersen J. I., Björkhem I., Gustafsson J. 26-Hydroxylation of C27-steroids by soluble liver mitochondrial cytochrome P-450. J Biol Chem. 1979 Jul 25;254(14):6464–6469. [PubMed] [Google Scholar]
  24. Pedersen J. I., Godager H. K. Purification of NADPH-ferredoxin reductase from rat liver mitochondria. Biochim Biophys Acta. 1978 Jul 7;525(1):28–36. doi: 10.1016/0005-2744(78)90196-1. [DOI] [PubMed] [Google Scholar]
  25. Pedersen J. I., Holmberg I., Björkhem I. Reconstitution of vitamin D3 25-hydroxylase activity with a cytochrome P-450 preparation from rat liver mitochondria. FEBS Lett. 1979 Feb 15;98(2):394–398. doi: 10.1016/0014-5793(79)80225-2. [DOI] [PubMed] [Google Scholar]
  26. Popják G., Edmond J., Anet F. A., Easton N. R., Jr Carbon-13 NMR studies on cholesterol biosynthesized from [13C]mevalonates. J Am Chem Soc. 1977 Feb 2;99(3):931–935. doi: 10.1021/ja00445a041. [DOI] [PubMed] [Google Scholar]
  27. STAPLE E., RABINOWITZ J. L. Formation of trihydroxycoprostanic acid from cholesterol in man. Biochim Biophys Acta. 1962 Jun 4;59:735–736. doi: 10.1016/0006-3002(62)90663-7. [DOI] [PubMed] [Google Scholar]
  28. Salen G. Cholestanol deposition in cerebrotendinous xanthomatosis. A possible mechanism. Ann Intern Med. 1971 Dec;75(6):843–851. doi: 10.7326/0003-4819-75-6-843. [DOI] [PubMed] [Google Scholar]
  29. Salen G., Shefer S., Cheng F. W., Dayal B., Batta A. K., Tint G. S. Cholic acid biosynthesis: the enzymatic defect in cerebrotendinous xanthomatosis. J Clin Invest. 1979 Jan;63(1):38–44. doi: 10.1172/JCI109275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Salen G., Shefer S., Setoguchi T., Mosbach E. H. Bile alcohol metabolism in man. Conversion of 5beta-cholestane-3alpha, 7alpha,12alpha, 25-tetrol to cholic acid. J Clin Invest. 1975 Jul;56(1):226–231. doi: 10.1172/JCI108071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schreiner A., Hopen G., Skrede S. Cerebrotendinous xanthomatosis (cholestanolosis). Investigations on two sisters and their family. Acta Neurol Scand. 1975 May;51(5):405–416. [PubMed] [Google Scholar]
  32. Schwartz C. C., Cohen B. I., Vlahcevic Z. R., Gregory D. H., Halloran L. G., Kuramoto T., Mosbach E. H., Swell L. Quantitative aspects of the conversion of 5 beta-cholestane intermediates to bile acids in man. J Biol Chem. 1976 Oct 25;251(20):6308–6314. [PubMed] [Google Scholar]
  33. Setoguchi T., Salen G., Tint G. S., Mosbach E. H. A biochemical abnormality in cerebrotendinous xanthomatosis. Impairment of bile acid biosynthesis associated with incomplete degradation of the cholesterol side chain. J Clin Invest. 1974 May;53(5):1393–1401. doi: 10.1172/JCI107688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shefer S., Cheng F. W., Batta A. K., Dayal B., Tint G. S., Salen G. Biosynthesis of chenodeoxycholic acid in man: stereospecific side-chain hydroxylations of 5beta-cholestane-3alpha,7alpha-diol. J Clin Invest. 1978 Sep;62(3):539–545. doi: 10.1172/JCI109158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shefer S., Cheng F. W., Dayal B., Hauser S., Tint G. S., Salen G., Mosbach E. H. A 25-hydroxylation pathway of cholic acid biosynthesis in man and rat. J Clin Invest. 1976 Apr;57(4):897–903. doi: 10.1172/JCI108366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Taniguchi S., Hoshita N., Okuda K. Enzymatic characteristics of CO-sensitive 26-hydroxylase system for 5beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol in rat-liver mitochondria and its intramitochondrial localization. Eur J Biochem. 1973 Dec 17;40(2):607–617. doi: 10.1111/j.1432-1033.1973.tb03233.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES