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

Abstract

A B S T R A C T Bile acid production in cerebrotendinous xanthomatosis (CTX) is subnormal, yet the activity of cholesterol 7a-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, 5,f-cholestane-3a,7a,12a, 25-tetrol and 5f8-cholestane-3a,7a,12a,24E,25-pentol. After i.v. injection of [4-'C]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.

Biosynthesis of bile acids in man. Hydroxylation of the C27-steroid side chain.

“…As shown in the present work, the microsomal 25-hydroxylase appears to be specific for 5P-cholestane-3a,7a,12a-triol. This finding can be considered as support for the conclusion by Mosbach and Salen (25) that patients with cerebrotendinous xanthomatosis utilize pathways to cholic acid involving 25-hydroxylation, and explains why these patients have an abnormally high cholic acid/ chenodeoxycholic acid ratio in bile (13).…”

A 25-hydroxylation pathway of cholic acid biosynthesis in man and rat.

“…Of particular importance in this respect are the findings by Cronholm and Johansson in the rat (2) and by Bjorkhem et al in man (8) that the major product formed during the incubation of 5,8-cholestane-3a,7a,12a-triol with liver microsomes was 5Pt-cholestane-3a,7a,12a,-25-tetrol and not 5,3-cholestane-3a,7a,12a,26-tetrol. Our own studies have shown that patients with cerebrotendinous xanthomatosis (CTX)' accumulate 25-hydroxylated bile alcohols in bile and feces (9), and that 5f-cholestane-3a,7a,12a,25-tetrol is transformed into cholic acid both in CTX patients and in normolipidemic subjects (10), a result previously reported by Yamada in the rat (11). While it was known, therefore, that 5j-cholestane3a,7a,12a-triol can be converted to 5,8-cholestane-3a,7a,-12a,25-tetrol in vitro and that the latter could be metabolized to cholic acid in vivo, the individual steps of this pathway remained to be demonstrated.…”

Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.

“…Total bile acid synthesis as measured by the sterol balance method was reduced 50% (8). Although the exact enzymatic defect in bile acid synthesis in CTX has not been defined completely, the major biochemical abnormality apparently involves the incomplete oxidation of the cholesterol side chain (4). The accumulation of C27 bile alcohols that are 12a-hydroxylated suggests that cholic acid synthesis is impaired, while the deficiency of chenodeoxycholic acid in the bile points to reduced formation of this primary bile acid.…”

“…The abnormalities include a marked deficiency of chenodeoxycholic acid in the bile and the excretion of large quantities of bile alcohols that contained 27 carbons in the bile, urine, and feces (3)(4)(5)(6)(7). Virtually all of these bile alcohols are hydroxylated at C-12 and C-25 and when excreted in urine and bile are conjugated at C-3 with glucuronic acid (6,7).…”