A novel pathway for biosynthesis of cholestanol with 7 alpha-hydroxylated C27-steroids as intermediates, and its importance for the accumulation of cholestanol in cerebrotendinous xanthomatosis.
A mixture of 7 alpha-3H- and 4-14C-labeled cholesterol was administered intravenously to rats. Cholestanol with 20-30% lower ratio between 3H and 14C than in cholesterol could be isolated from different organs. In a healthy human control, cholestanol isolated from feces had a 3H/14C ratio which was 28% lower than in administered cholesterol. Cholesterol and coprostanol reisolated in these experiments had the same ratio between 3H and 14C as in the precursor. A previously unknown pathway for formation of cholestanol, involving 7 alpha-hydroxylated intermediates, may explain these results. Under normal conditions, this pathway is responsible for at most 30% of the cholestanol synthesized from cholesterol. Intravenous administration of the 7 alpha-3H- and 4-14C-labeled cholesterol to a patient with cerebrotendinous xanthomatosis (CTX) resulted in formation of cholestanol which had 70-75% lower 3H/14C ratio. It is concluded that the novel pathway involving 7 alpha-hydroxylated intermediates is accelerated in patients with CTX. This acceleration may contribute essentially to the accumulation of cholestanol, which is a predominant feature of this disease. 7 alpha-Hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one might be intermediates in the novel pathway to cholestanol. After intravenous administration of 7 beta-3H-labeled 7 alpha-hydroxycholesterol in a patient with CTX, significant amounts of 3H were incorporated into plasma and fecal cholestanol. Only small amounts of 7 alpha-hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one are excreted into the intestine, and we therefore conclude that the 7 alpha-dehydroxylation step mainly occurs in the liver. In CTX, the synthesis of cholestanol may be accelerated because the concentrations of 7 alpha-hydroxylated bile acid intermediates in the liver are increased. A possible mechanism for the conversion of a minor fraction of 7 alpha-hydroxycholesterol into cholestanol is suggested.
D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism; D001927:Brain Diseases / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004083:Cholestanol / Q000096:biosynthesis* / Q000378:metabolism; D002777:Cholestanols / Q000096:biosynthesis*; D002784:Cholesterol / Q000031:analogs & derivatives*; D005243:Feces / Q000032:analysis; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008875:Middle Aged; D009135:Muscular Diseases / Q000378:metabolism*; D014973:Xanthomatosis / Q000378:metabolism*
D001647:Bile Acids and Salts; D002777:Cholestanols; D004083:Cholestanol; D002784:Cholesterol