Abstract

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)