Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1974 May;53(5):1393–1401. doi: 10.1172/JCI107688

A Biochemical Abnormality in Cerebrotendinous Xanthomatosis IMPAIRMENT OF BILE ACID BIOSYNTHESIS ASSOCIATED WITH INCOMPLETE DEGRADATION OF THE CHOLESTEROL SIDE CHAIN

T Setoguchi 1,2,3,4, Gerald Salen 1,2,3,4, G S Tint 1,2,3,4, E H Mosbach 1,2,3,4
PMCID: PMC302628  PMID: 4825231

Abstract

Bile acid production in cerebrotendinous xanthomatosis (CTX) is subnormal, yet the activity of cholesterol 7α-hydroxylase, the rate-determining enzyme of bile acid synthesis, is elevated. To explain this discrepancy, bile acid precursors were sought in bile and feces of three CTX subjects. Over 10% of the total sterols excreted in bile and feces consisted of compounds more polar than cholesterol. Chromatographic analysis of the polar fractions in conjunction with gasliquid chromatography (GLC)-mass spectrometry indicated two major constituents, 5β-cholestane-3α,7α,12α,25-tetrol and 5β-cholestane-3α,7α,12α,24ξ,25-pentol. After i.v. injection of [4-14C]cholesterol both bile alcohols were radioactive proving that they were derived from cholesterol. The accumulation of alcohols hydroxylated at C-25 and C-24,25 suggests that decreased bile acid synthesis in CTX results from impaired oxidation of the cholesterol side chain. This finding and the virtual absence of intermediates hydroxylated at C-26 indicate that current views of the major pathway of bile acid synthesis may require revision.

Full text

PDF
1393

Selected References

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

  1. 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]
  2. Diekman J., Djerassi C. Mass spectrometry in structural and stereochemical problems. CXXV. Mass spectrometry of some steroid trimethylsilyl ethers. J Org Chem. 1967 Apr;32(4):1005–1012. doi: 10.1021/jo01279a033. [DOI] [PubMed] [Google Scholar]
  3. Goodman D. S., Noble R. P., Dell R. B. Three-pool model of the long-term turnover of plasma cholesterol in man. J Lipid Res. 1973 Mar;14(2):178–188. [PubMed] [Google Scholar]
  4. Grundy S. M., Ahrens E. H., Jr Measurements of cholesterol turnover, synthesis, and absorption in man, carried out by isotope kinetic and sterol balance methods. J Lipid Res. 1969 Jan;10(1):91–107. [PubMed] [Google Scholar]
  5. HOSHITA T. Stero-bile acids and bile sterols. 47. Syntheses of 3alpha,7alpha,12alpha,25,26- and 3alpha,7alpha,12alpha,24,25-pentahydroxycoprostanes. J Biochem. 1962 Sep;52:176–179. doi: 10.1093/oxfordjournals.jbchem.a127593. [DOI] [PubMed] [Google Scholar]
  6. Mosbach E. H. Hepatic synthesis of bile acids. Biochemical steps and mechanisms of rate control. Arch Intern Med. 1972 Oct;130(4):478–487. [PubMed] [Google Scholar]
  7. Nicolau G., Shefer S., Salen G., Mosbach E. H. Determination of hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in man. J Lipid Res. 1974 Jan;15(1):94–98. [PubMed] [Google Scholar]
  8. 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]
  9. Salen G., Grundy S. M. The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. J Clin Invest. 1973 Nov;52(11):2822–2835. doi: 10.1172/JCI107478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Salen G., Polito A. Biosynthesis of 5 -cholestan-3 -ol in cerebrotendinous xanthomatosis. J Clin Invest. 1972 Jan;51(1):134–140. doi: 10.1172/JCI106783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Samuel P., Lieberman S. Improved estimation of body masses and turnover of cholesterol by computerized input--output analysis. J Lipid Res. 1973 Mar;14(2):189–196. [PubMed] [Google Scholar]
  12. Suda T., DeLuca H. F., Schnoes H., Blunt J. W. 25-hydroxyergocalciferol: a biologically active metabolite of vitamin D2. Biochem Biophys Res Commun. 1969 Apr 29;35(2):182–185. doi: 10.1016/0006-291x(69)90264-2. [DOI] [PubMed] [Google Scholar]
  13. WHITEHOUSE M. W., STAPLE E., GURIN S. Catabolism in vitro of cholesterol. III. Oxidation of 3 alpha, 7 alpha, 12 alpha-trihydroxy-coprostane, 3 alpha, 7 alpha, 12 alpha-trihydroxy-24-ketocoprostane, and 3 alpha, 7 alpha, 12 alpha, 24-tetrahydroxycoprostane by rat liver mitochondria. J Biol Chem. 1961 Jan;236:73–75. [PubMed] [Google Scholar]
  14. Yamada T. Stero-bile acids and bile alcohols. 93. Metabolism of 5-beta-cholestane-3-alpha, 7-alpha, 12-alpha, 25-tetrol. Hiroshima J Med Sci. 1966 Dec;15(4):375–390. [PubMed] [Google Scholar]

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

RESOURCES