Abstract
24-Norursodeoxycholic acid (nor-UDCA), when administered into the anesthetized biliary fistula hamster or injected into the perfusate of an isolated liver, was hydroxylated at C-5 to give 5 beta-hydroxynorursodeoxycholic acid 2 (3 alpha,5,7 beta-trihydroxy-24-nor-5 beta-cholan-23-oic acid), which was secreted into bile mainly as such. Similarly, 24-norchenodeoxycholic acid (nor-CDCA) was 5 beta-hydroxylated to give 5 beta-hydroxynor-chenodeoxycholic acid 4 (3 alpha,5,7 alpha-trihydroxy-24-nor-5 beta-cholan-23-oic acid), which was also secreted into bile without appreciable further biotransformation. The site of hydroxylation was assigned by 13C and 1H NMR and mass spectrometry. 5-Hydroxylation was a major biotransformation pathway at physiological bile acid loads. 5-Hydroxylation of UDCA also occurred in the perfused rat liver but to a lesser extent. 5-Hydroxylation of nor-UDCA was not observed in rabbit, dog, or man, indicating that its formation is species-specific. 5-Hydroxylation of nor-CDCA and nor-UDCA is the first reported example of hydroxylation of a tertiary carbon atom of bile acids. Nor-dihydroxy bile acids appear to be useful for the detection of minor hydroxylation pathways, because their prolonged hepatobiliary retention exposes them repeatedly to hydroxylases present in the hepatobiliary system.
Highlights
24-Norursodeoxycholic acid, when ad- from that of cholic acid, which like other common natural c24 ministered into the anesthetized biliary fistulahamster bile acids, undergoes efficient N-acylation withtaurine during or injected into the perfusate of an isolated liver, was hepatic transport (4-7)
Therearenopublishedstudies of massspectra of C-5. These data indicate that thetwo nor-dihydroxy bile acids, nor-UDCA 1 and nor-CDCA 3,were hydroxylated in the 5P position of the steroidal nucleus togive 2 and 4, respectively
The final productwas a more polar trihydroxy compound which was secreted into bile without undergoing hydroxy bile acids, mass spectra of TMS ethers of cholestane-3,5-diolshavebeenreported (44, 45)
Summary
Appear to be useful for the detection of minor hydroxylation pathways, because their prolonged hepatobili-. Nor-bile acids are homologues of the natural Cz4bile acids prepared by the method of Tserng and Klein (10); [2,4-3H]nor-CDCA in which the side chain has been shortened by one carbon atom. Such compounds occur naturally in trace proportions in bile (1)and urine (2) of healthy humans. For studies of their metabolism, such compounds are usually prepared synthetically by degradation of the side chain of natural bile (specific activity, 1mCi/mmol) was prepared according to Ref. 11;all were purified by preparative TLC on silica gel and were more than 99% pure by radio-HPLC (12). Acids; aconvenientsynthesis of these bile acids has been reported recently from this laboratory (3)
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