A novel route for the biosynthesis of cholestanol, and its significance for the pathogenesis of cerebrotendinous xanthomatosis.

The main symptoms in cerebrotendinous xanthomatosis (CTX) are caused by increased synthesis of cholestanol (5 alpha-cholestan-3 beta-ol) and depositions of this steroid in brain and xanthomas. Previously, we have shown a deficiency in CTX of the mitochondrial C27-steroid 26-hydroxylase essential for normal degradation of the cholesterol side chain. Because of this defect, different 7 alpha-hydroxylated substrates for the 26-hydroxylase accumulate in the liver - among these 7 alpha-hydroxy-4-cholesten-3-one. The possibility that such accumulated 7 alpha-hydroxylated bile acid precursors can be converted into cholestanol was studied by administration of labelled 7 alpha-hydroxy-cholesterol to bile fistula rats and to a patient with CTX. Label was incorporated into cholestanol in the rats as well as in the CTX-patient. The quantitative significance of this 7 alpha-hydroxylation/dehydroxylation route for the biosynthesis of cholestanol was examined by administering a mixture of 7 alpha-3H and 4-14C-labeled cholesterol to rats, rabbits and a human volunteer. In all species, about 25% of 3H was lost during the conversion of cholesterol to cholestanol. In a patient with CTX, the flow through the 7 alpha-hydroxylation/dehydroxylation route was greatly increased, since 75% of 3H present in the precursor (cholesterol) had been removed in cholestanol isolated from bile, serum and faeces. Experiments with germfree rats and bile fistula rats indicate that the 7 alpha-dehydroxylation mainly occurs in the liver. The microsomal fraction of rat liver was found to 7 alpha-dehydroxylate 7 alpha-hydroxy-4-cholesten-3-one at a slow rate.(ABSTRACT TRUNCATED AT 250 WORDS)