Hepatic 7 alpha-dehydroxylation of bile acid intermediates, and its significance for the pathogenesis of cerebrotendinous xanthomatosis.

The bile acid precursor 7 alpha-hydroxy-4-cholesten-3-one was found to be enzymatically dehydroxylated at a slow rate by liver tissues from the rat, human, and guinea pig. The rat liver enzyme is localized in the microsomal fraction, has a pH optimum of about 8.5, an apparent Km of 0.03-0.04 mM, and a Vmax of 10-15 nmoles.mg protein-1.hr-1. The product from 7 alpha-hydroxy-4-cholesten-3-one was identified as cholesta-4,6-dien-3-one by its chromatographic properties and by mass spectrometry. The reaction proceeded both in air and N2, and pyridine nucleotides were not required as cofactors. In addition to the enzymatic reaction, there was a significant nonenzymatic dehydroxylation of 7 alpha-hydroxy-4-cholesten-3-one, in particular at high pH and with high concentrations of protein. No 7 alpha-dehydroxylation occurred with various 7 alpha-hydroxylated 3 beta-hydroxy-delta 5-steroids. We have previously shown that at least part of the accumulation of cholestanol in cerebrotendinous xanthomatosis (CTX) is due to accelerated 7 alpha-dehydroxylation of bile acid intermediate(s), which are further converted into cholestanol. The capacity to dehydroxylate 7 alpha-hydroxy-4-cholesten-3-one was found to be about the same in homogenates of liver biopsies from two patients with CTX as in preparations from control subjects. It is suggested that increased levels of substrate (7 alpha-hydroxy-4-cholesten-3-one) in the liver, rather than increased amounts of 7 alpha-dehydroxylase is the explanation for the accelerated 7 alpha-dehydroxylation in CTX that leads to increased biosynthesis of cholestanol.