Abstract
We previously reported that the 7 alpha-dehydroxylation of cholic acid appears to be carried out by a multi-step pathway in intestinal anaerobic bacteria both in vitro and in vivo. The pathway is hypothesized to involve an initial oxidation of the 3 alpha-hydroxy group and the introduction of a double bond at C4-C5 generating a 3-oxo-4-cholenoic bile acid intermediate. The loss of water generates a 3-oxo-4,6-choldienoic bile acid which is reduced (three steps) yielding deoxycholic acid. We synthesized, in radiolabel, the following putative bile acid intermediates of this pathway 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acid, 7 alpha,12 alpha-dihydroxy-3-oxo-5 beta-cholanoic acid, 12 alpha-dihydroxy-3-oxo-4,6-choldienoic acid, and 12 alpha-hydroxy-3-oxo-4-cholenoic acid and showed that they could be converted to 3 alpha,12 alpha-dihydroxy-5 beta-cholanoic acid (deoxycholic acid) by whole cells or cell extracts of Eubacterium sp. VPI 12708. During studies of this pathway, we discovered the accumulation of two unidentified bile acid intermediates formed from cholic acid. These bile acids were purified by thin-layer chromatography and identified by gas-liquid chromatography-mass spectrometry as 12 alpha-hydroxy-3-oxo-5 alpha-cholanoic acid and 3 alpha,12 alpha-dihydroxy-5 alpha-cholanoic (allo-deoxycholic acid). Allo-deoxycholic acid was formed only in cell extracts prepared from bacteria induced by cholic acid, suggesting that their formation may be a branch of the cholic acid 7 alpha-dehydroxylation pathway in this bacterium.
Highlights
We previously reported that the 7a-dehydroxylation of cholic acid appears to be carried out by a multi-step pathway in intestinal anaerobic bacteria both in vitro and in vivo
We have demonstrated that deoxycholic acid is converteidnt1o2a-hydroxy-3-oxo-4
We proposed that this compound may be an intermediateinbileacid7a-dehydroxylation.Inaddition, we showed that [3P-3H]- and[5/3-3H]-labeled cholic acid lose the tritium during the conversion into deoxycholic acid both in vitro and invivo studies in humans [6]
Summary
We previously reported that the 7a-dehydroxylation of cholic acid appears to be carried out by a multi-step pathway in intestinal anaerobic bacteria both in vitro and in vivo. During studies of this pathway,we discovered the accumulation oftwo unidentified bileacid intermediates formedfromcholicacid These bileacidswere purified by thin-layer chromatography and identified bygasliquid chromatography-mass spectrometry as 12a-hydroxy-3oxo-5a-cholanoicacid and 3a,l2a-dihydroxy-5a-cholanoi(callodeoxycholic acid). Cholenoicacid while linkedtoanadenosinenucleotide [5] We proposed that this compound may be an intermediateinbileacid7a-dehydroxylation.Inaddition, we showed that [3P-3H]- and[5/3-3H]-labeled cholic acid lose the tritium during the conversion into deoxycholic acid both in vitro and invivo studies in humans [6]. Based on this information, we proposed that the mechanismof bile acid 7a-dehydroxylation involves a n initial two-step oxidation of theprimary bile acidgenerating a 3-oxo-A*-
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