Formation of alio bile acids in the liver

5a-Bile acids (alio bile acids) are minor constituents in mammalian bile, ranging from 17c or less in man to more than 5% in rabbits. In several lower vertebrates, alio bile acids are the major bile acids (Chapter 10). Three different pathways have been described for formation of alio bile acids. 

Deoxycholic acid can be converted into allodeoxycholic acid in rabbits and rats [159,160], Kallner has shown that this conversion probably occurs by intermediate formation of the corresponding 3-oxo-5/8-, S-oxo-A - and 3-oxo-5a-bile acids [161,162]. Most or all of these reactions are catalysed by intestinal microorganisms. The reactions are reversible and it has been shown that allocholic, allo-chenodeoxycholic, allodeoxycholic and allolithocholic acid can be converted into the corresponding 5j8-bile acids. 

Bjorkhem and Einarsson showed that rat liver microsomes in the presence of NADPH are able to convert 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one into the corresponding 3-oxo-5a-steroids (Fig. 11) [168], Liver microsomes from female rats were 3-4 times more active than those from male rats. A similar sex difference was not found in human hver microsomes. The 3-oxo-5a-steroids were efficiently converted into alio bile acids in bile fistula rats. In the presence of both NADPH and NADH, the 3-oxo-5a-steroids were converted into the corresponding 3/3-hydroxy-5a-steroids. As mentioned above, the 3-oxo-5a-steroids are efficiently converted into the corresponding 3a-hydroxy-5a-steroids in the cytosol. 

In the microsomal 5 a saturation of the double bond in 7a-hydroxy-4-cholesten-3-one there is a stereospecific transfer of a hydride ion from the 4B position of NADPH to the 5 a position of the steroid [169]. From the results of experiments on the stereochemistry of the addition of the proton to the 4 position, it was concluded that the reduction of the double bond is likely to involve a non-stereospecific addition of hydrogens or a cis addition rather than a trans addition. 

The quantitative importance of the pathway involving 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one as intermediates in formation of alio bile acids is not known. At least in the rat, the capacity of the microsomal A -3-oxosteroid 5a-reductase is high, and thus it is surprising that such small amounts of alio bile acids are formed under normal conditions in mammals. It seems probable that this enzyme is inhibited under in vivo conditions. Hoshita et al. found an efficient conversion of 7a,12a-dihydroxy-4-cholesten-3-one into 7a,12a-dihy-droxy-5a-cholestan-3-one in the microsomal fraction of liver from Iguana iguana [170], Alio bile acids are predominant in this species of iguana and it was suggested that the microsomal A -3-oxosteroid 5a-reductase is of major importance for their formation. 

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