Dihydroxycoprostanic acid

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

Table 5.4.3 Reproducibility of total analysis determined with 200-pl aliquots of fasting adult plasma (n = 8 reprinted from [18]). DHCA Dihydroxycoprostanic acid, THCA trihydroxycoprostanic acid...

Table 5.4.5 Concentrations of BAs and the ratios THCA/CA and DHCA/CDCA in adult fasting plasma (n = 10 reprinted from [18]). 3( 5 3f>-Hydroxychol-5-enic acid, HCA dihydroxycoprostanic acid, UDCA ursodeoxycholic acid...

There are two 24-carbon primary bile acids in man, cholic and chenode-oxycholic acids, shown as compounds I and II, respectively, in Fig. 1. There are two 27-carbon bile acids in human bile, trihydroxycoprostanic acid. III, and dihydroxycoprostanic acid, IV. These may also be regarded as primary bile acids, but they occur in very small quantities compared to the amounts of 24-carbon bile acids and consequently the term primary bile acids usually refers to the two 24-carbon bile acids in man, cholic and chenode-oxycholic. 

The pathways for primary bile salt synthesis shown in Fig. 2 are derived from studies in man (3-7) and are believed to represent the major synthetic routes. Several of the intermediates shown in Fig. 2 have been isolated from human bile. Trihydroxycoprostanic acid, XV, has been crystallized from human fistula bile (8) and shown to be derived from cholesterol (4,5). The major metabolite of trihydroxycoprostanic acid in man is cholic acid (5). 5/5-Cholestane-3a,7a-diol, X, has been identified as a product of cholesterol oxidation (6) and 3a,7a-dihydroxycoprostanic acid, XI, has been isolated from human fistula bile (7). 

It seems quite apparent that 7a-OH-cholesterol serves as a primary intermediate in human chenodeoxycholic acid synthesis (1). 5 -cholestane-3a,7a-diol and, further, dihydroxycoprostanic acid have been found in human bile (17). The latter is known to be converted finally to chenodeoxy-cholate (18). Thus dihydroxycoprostanic acid belongs to the primary human bile acids. 

The only dihydroxycoprostanic acid thus far identified as a natural product was isolated from alligator bile by Dean and Whitehouse (169) and from human bile by Carey et al. (170). The acid was characterized by comparison with synthetic material (169, 171). 

Another hydroxylation role for vitamin C in the hepatic microsomal fraction is the stepwise conversion of cholesterol to the bile acid, cholic acid, via 7a-hydroxycholesterol, 3a,7a-dihydroxycoprostane and 3a,7a,12o-trihydroxycoprostane. Also, in lipid metabolism, conventional fatty acids with an even number of carbon atoms are a-oxidised by a mono-oxygenase and subsequently decarboxylated to form an odd-numbered carbon derivative and both these steps appear to require ascorbic acid. As the initial a-oxidation is brought about by a... 

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