3,4-Seco-12α-hydroxy-5β-cholan-3,4,24-trioic Acid, a Novel Secondary Bile Acid: Isolation from the Bile of the Common Ringtail Possum (Pseudocheirus peregrinus) and Chemical Synthesis

Isolation and Identification of 3,4-Seco-Solanidine-3,4-dioic Acid as a Urinary Biomarker of CYP2D6 Activity

“…Verhoeven and coworkers reported A-ring opening of a progestogen, (17α)-17-hydroxy-11-methylene-19norpregna-4,15-dien-20-yn-3-one, was the major metabolic route after oral administration of the compound to rats (Verhoeven et al, 1998), and Lai et al (Lai et al, 2011) reported on the oxidation and opening of a keto-piperidine group of a poly(ADP-ribose) polymerase inhibitor; in the latter study, in vitro experiments revealed FMO5 to be responsible for the ring-opening via Baeyer-Villiger oxidation. Finally, a novel secondary bile acid in the common ring tail possum was recently described and mimics the exact A-ring opening that we observed (Sekiguchi et al, 2017). A-ring scission through a Baeyer-Villiger mechanism and oxidation of the resulting alcohol (following hydrolysis) to the carboxylate is a multistep process.…”

“…Secondly the 13 C{ 1 H} chemical shifts for C-3 and C-4 are δ 181.5 and 174.1, respectively, and correspond very well to reported chemical shifts of carboxylic acid moieties in C 27 products. For example 3,4-seco-12α-hydroxy-5β-cholan-3,4,24-trioic acid, a bile acid produced from cholesterol metabolism, has been synthesized and characterized using NMR techniques (Sekiguchi et al, 2017). Its reported 13 C{ 1 H} chemical shifts for C-3 and C-4 are δ 176.4 and δ 177.2, respectively.…”

“…In fact, incubation of solanidine with heterologously expressed CYP2D6 produced a hydroxylated metabolite that has been identified as 4-hydroxysolanidine by an NMR analysis approach analogous to that described for SSDA (manuscript in preparation), a significant finding in that 3-keto-4-hydroxy compounds are potential substrates for Baeyer-Villiger oxidations as discussed above. Based on the reported trans-cyclohexa-1,2-diol to adipate pathway ( (Davey and Trudgill, 1977); Figure 4A) and the reports of 3,4-seco-12α-hydroxy-5β-cholan-3,4,24-trioic acid formed from a secondary bile acid ((Sekiguchi et al, 2017); Figure 4B) and 4-hydroxy-3,4-seco-tomatidine-3-oic acid from tomatidine ((Gaberc-Porekar et al, 1983); Figure 4C), we propose a pathway for formation of SSDA from solanidine following CYP2D6-mediated formation of 4-hydroxysolanidine in Figure 4D.…”

“…A. Proposed pathway for adipic acid formation from trans-cyclohexa-1,2-diol(Davey and Trudgill, 1977); B. A-ring opening to form 3,4-seco-12α-hydroxy-5β-cholan-3,4,24-trioic acid formed from deoxycholic acid(Sekiguchi et al, 2017); C. Formation of 4hydroxy-3,4-seco-tomatidine-3-oic acid from tomatidine(Gaberc-Porekar et al, 1983); D.…”