Trihydroxycoprostanic 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...

C5. Carey,. B., Conversion of cholesterol to trihydroxycoprostanic acid and cholic acid in man. J. Clin. Invest. 43, 1443-1448 (1964). 

E5. Eyssen, H., Parmentier, G., Compemolle, F., Boon, J., and Eggermont, E., Trihydroxycoprostanic acid in the duodenal fluid of two children with intrahepatic bile duct anomalies. Biochim. Biophys. Acta 273, 212-221 (1972). 

Investigation of the 3-hydroxyacyl-CoA dehydrogenase activities in purified rat liver peroxisomes, using the 3-hydroxyacyl-CoAs of straight chain fatty acids, of 2-methyl-branched chain fatty acids and of trihydroxycoprostanic acid as substrates, revealed initially 5 different enzymes (named I to V)." Enzyme IV was a monomeric 78 kD protein, possessed crotonase activity, was induced by clofibrate, and was identified as the inducible multifunctional protein. Interestingly, enzyme III, a monomeric 80 kD protein, also hydrated crotonyl-CoA. In contrast to enzyme IV, enzyme III was not induced by clofibrate." This was the first indication, pubhshed in 1994, that peroxisomes contained a second multifunctional protein. It was named multifunctional protein 2 (MFP-2) (the inducible, firstly isolated protein is referred to as MFP-1). Based on its substrate spectrum, the newly identified multifunctional protein was postulated to be involved in bile acid formation. ... 

Due to a stereospecific hydroxylation step during the co-oxidation of cholesterol, only 25R-trihydroxycoprostanic acid is formed. After activation it needs to be converted to 25S-THC-CoA since THCCox acts only on the 25S- isomer, a finding confirmed by others. Most likely, racemisation of THC-CoA and pristanoyl-CoA is catalyzed by the same enzymes. Recently, the cloning of the (putatively peroxisomal) rat and mouse racemase was reported. Apparently, it is identical to 2-aryl-propionyl-CoA epimerase. ... 

ALDP adrenoleukodystrophy protein BRCA- branched chain acyl- C24 ligno-ceric acid THCA trihydroxycoprostanic acid THC- trihydroxycoprostanoyl-. 

G. P. (1993) J. Biol. Chem. 268, 10335-10344. The CoA esters of 2-melhyl-branched chain fatty acids and of the bile acid intermediates di- and trihydroxycoprostanic acids are oxidized by one single peroxisomal branched chain acyl-CoA oxidase in human liver and kidney. 

Dieuaide-Noubhani, M., Novikov, O.K., Baumgart, E., Vanhooren, J.C.T, Fransen, M., Goethals, M., Vandekerckhove, J., Van Veldhoven, P.P. Mannaerts, G.P. ( 9%)Eur. J. Biochem24(i, 660-666. Further characterization of the peroxisomal 3-hydroxyacyl-CoA dehydrogenases from rat liver relationship between the different dehydrogenases and evidence that fatty acids and the C27 bile acids di- and trihydroxycoprostanic acids are metabolized by separate multifunctional proteins. 

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). 

The synthesis of cholic acid from cholesterol in rodents proceeds via 7a-OH-cholesterol, leading to a trihydroxy derivative which finally loses a side chain, resulting in the formation of cholic acid (1). The synthesis appears to proceed similarly in the human liver (12). Trihydroxycoprostanic acid, which is a precursor of cholic acid and which is formed from cholesterol... 

Some of the early investigations into the nature of bile acids in the bile of older vertebrates suggested the existence of acidic sterols more closely related to cholesterol than to cholic acid. Kurauti and Kazuno (45) isolated a bile acid from the bile of the frog, Rana catesbiana, which was later found to be an isomer of 3a,7a,12a-trihydroxycoprostanic acid (XI) (Fig. 7). This latter acid, possessing 27 carbon atoms, was isolated by Haslewood (46) in 1952 from the bile of the crocodile. Alligator mississippiensis. The inability to oxidize the side chain of C27 acids to C24 acids is regarded as a primitive characteristic in the biochemical evolution of the bile acids (for a fuller... 

Fig. 7. 3a ,7a,l2a-trihydroxycoprostanic acid (XI) 3rt,7 ,12n-trihydroxy-24-methyl-d -coprostenic acid (trihydroxybufostero-cholanic acid) (XII). 

This alcohol has been isolated from the bile of the carp (228). It may be the alcohol isolated much earlier from the toad Bufo vulgaris japonica) by Makino (229) and named tetrahydroxybufostane (194). 27-Deoxy-5a-cyprinol was prepared from anhydrocyprinol by Hoshita (230). Its 5,3-epimer may be an expected intermediate in the formation of trihydroxycoprostanic acid, but the alcohol has not been widely found. Both the 5 - and 5 -epimers of 27-deoxycyprinol were formed in toads given C-cholesterol (194). 

When trihydroxycoprostanic acid labeled in the 4 position (prepared in the same manner as the 26-labeled acid) is incubated with rat liver mitochondria, labeled cholic acid is obtained. Danielsson had been carrying out parallel experiments in mouse liver mitochondria, and his work yielded valuable information concerning the pattern of hydroxylation of cholesterol. Cholesterol can be converted to 26 hydroxycholesterol and also to the 3/5, 7a, 26-triol. Danielsson also showed that liver mitochondrial preparations could convert 3 a, 7 a, 12 a trihydroxy coprostane to 3a, 7 a, 12 a, 26-tetrahydroxycoprostane, 3 a, 7 a, 12a-tri-... 

Metabolism of trihydroxycoprostanic acid formation from cholesterol in the alligator and conversion to cholic acid and carbon dioxide in vitro by rat liver mitochondria. J. biol. Chem. 236, 688 (1961). 

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