Species differences and alternative pathways in the biosynthesis of bile acids

Most of the studies referred to above have been performed on rats. In vitro and in vivo studies have shown that the major pathways in man are similar to although not necessarily identical to those in the rat. 

From in vitro experiments it may be concluded that there are several possible pathways for formation of chenodeoxycholic acid in rat liver. A number of different 26-hydroxylated steroids are converted into chenodeoxycholic acid in bile fistula 

Yamasaki et al. have studied a pathway for formation of chenodeoxycholic acid in the rat involving intermediate formation of 7a-hydroxycholesterol, 3 -hydroxy-5-cholenoic acid and 7a-hydroxy-3-oxo-4-cholenoic acid [176-179]. In this pathway, changes in the side chain occur after the rate-limiting step. From the data available, it is not possible to evaluate the quantitative importance of this pathway. 

Introduction of a 26-hydroxyl group almost completely prevents introduction of a 12 -hydroxyl group in rat liver. In contrast, there is an efficient conversion of 5)8-cholestane-3a,7a,26-triol and 7a,26-dihydroxy-4-cholesten-3-one into both cholic and chenodeoxychohc acid in human hver [180-182], From these findings it is possible to formulate a number of different pathways in the biosynthesis of cholic acid in human hver, with introduction of the 26- and the 12a-hydroxyl groups at different stages. 

Studies on patients with the rare inborn disease cerebrotendinous xanthomatosis provide unique possibilities to evaluate the relative importance of different intermediates as substrates for the mitochondrial 26-hydroxylase. These patients appear to have a complete lack of mitochondrial 26-hydroxylase activity and may thus be expected to accumulate the normal substrates for the 26-hydroxylase in their livers. According to an investigation by Bjbrkhem et al., in which the level of different intermediates in a hver biopsy was determined by isotope dilution-mass spectrometry, 7a-hydroxy-4-cholesten-3-one and 5 3-cholestane-3a,7a,12a-triol seem to be the most important normal substrates for the 26-hydroxylase also in man [183]. 

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XIII) Species differences and alternative pathways in the biosynthesis of bile acids... 

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