Bile acid synthetic defects

Bove KE, Daugherty CC, Tyson W, Mierau G, Heubi JE, Balistreri WF, Setchell KDR (2000) Bile acids synthetic defect and liver disease. Pediatr Dev Pathol 3 1-16 Hopfer U (2002) Digestion and absorption of basic nutritional constituents. In Devlin T (ed) Textbook of Biochemistry with Clinical Correlations. Wiley- Liss, New York, pp 1110-1113 Clark ML and Harries JT (1975) In McColl I, Sladen GE (eds) Intestinal Absorption in Man. Academic Press, New York, p. 195... 

Bove K, Heubi J, Balistreri W, Setchell (2004) Bile acid synthetic defects and liver disease a comprehensive review. Pediatr Dev Pathol 7 315-334... 

Hvdroxvlation pathway An alternative explanation for the bile acid synthetic defect in CTX has been proposed by Oftebro and colleagues which starts via 26-hydroxylation of 5P-cholestane-3a,7a,12a-triol (IX, Fig. lOa and 10b). In this pathway the mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (63) which can convert 5P-cholestane-3a,7a,12a-triol (IX ) to 5P-cholestane-3a,7a,12a,26-tetrol (XI) (Fig. 10a and 10b ). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid (THCA, XII) by liver cytosol (2,64). Further hydroxylation at C-24 forms varanic acid (XIV) and its side chain is shortened with oxidation at C-24 to yield cholic acid (X,Fig. 10 a). These investigators demonstrated diminished mitochondrial 26-hydroxylation of 5p-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol, possible precursors for cholic acid and chenodeoxycholec acid in CTX liver. As a consequence, neither 26-hydroxylated intermediates can be formed so that total primary bile acid synthesis would be diminished. Accordingly, the accumulation of 5P-cholestane-3a,7a,12a,25-tetrol arises from 25-hydroxylation of 5P-cholestane-3a,7a,12a-triol by the alternative microsomal 25-hydroxylation mechanism. 

In diagnoses of some rare conditions, such as bile acid synthetic defects, MS can also be utilized. Nowadays it is possible to screen and rapidly diagnose potential or real inborn errors in bile acid synthesis from urinary bile acid analysis by means of MS. Specific mutations in the genes that encode the enzymes responsible for bile acid synthesis can be identified by molecular techniques. Of the seven known genetic defects that cause progressive cholestatic Uver disease, syndromes of fat-soluble vitamin malabsorption, and neurological disease, six have been properly characterized [16]. 

Patients also develop cholesterol gallstones from a defect in bile acid synthesis. The defect is in the mitochondrial C27-steroid 27-hydroxylase. In these patients, the reduced formation of normal bile acids, particularly chenodeoxycholic acid, leads to the up-regulation of the rate limiting enzyme Tct-hydroxylase of the bile acid synthetic pathway (discussed later). This leads to accumulation of 7a-hydroxylated bile acid intermediates that are not normally utilized. 

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