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The Journal of Lipid Research, Vol. 39, 2452-2458, December 1998
Copyright © 1998 by Lipid Research, Inc.

Original Article

Sensitive analysis of serum 3, 7, 12,24-tetrahydroxy- 5ß-cholestan-26-oic acid diastereomers using gas chromatography–mass spectrometry and its application in peroxisomal D-bifunctional protein deficiency

Correspondence to: P. Vreken.

The final steps in bile acid biosynthesis take place in peroxisomes and involve oxidative cleavage of the side chain of C₂₇-5ß-cholestanoic acids leading to the formation of the primary bile acids cholic acid and chenodeoxycholic acid. The enoyl-CoA hydratase and ß-hydroxy acyl-CoA dehydrogenase reactions involved in the chain shortening of C₂₇-5ß-cholestanoic acids are catalyzed by the recently identified peroxisomal D-bifunctional protein. Deficiencies of D-bifunctional protein lead, among others, to an accumulation of 3,7,12,24-tetrahydroxy-5ß-cholest-26-oic acid (varanic acid). The ability to resolve the four C₂₄, C₂₅ diastereomers of varanic acid has, so far, only been carried out on biliary bile acids using p -bromophenacyl derivatives. Here, we describe a sensitive gas chromatography–mass spectrometry (GC/MS) method that enables good separation of the four varanic acid diastereomers by use of 2R-butylester-trimethylsilylether derivatives. This method showed the specific accumulation of (24R,25R)-varanic acid in the serum of a patient with isolated deficiency of the D-3-hydroxy acyl-CoA dehydrogenase part of peroxisomal D-bifunctional protein, whereas this diastereomer was absent in a serum sample from a patient suffering from complete D-bifunctional protein deficiency. In samples from both patients an accumulation of (24S,25S)-varanic acid was observed, most likely due to the action of L-bifunctional protein on 24E-THCA-CoA. This GC/MS method is applicable to serum samples, obviating the use of bile fluid, and is a helpful tool in the subclassification of patients with peroxisomal D-bifunctional protein deficiency.—Vreken, P., A. van Rooij, S. Denis, E. G. van Grunsven, D. A. Cuebas, and R. J. A. Wanders. Sensitive analysis of serum 3,7,12,24-tetrahydroxy-5ß-cholestan-26-oic acid diastereomers using gas chromatography–mass spectrometry and its application in peroxisomal D-bifunctional protein deficiency. J. Lipid Res. 1998. 39: 2452–2458.

Supplementary key words: peroxisome, bile acids, D-bifunctional protein, GC/MS

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