Journal of Lipid Research, Vol 28, 1384-1397, Copyright © 1987 by Lipid Research, Inc.
Bile acids with a cyclopropyl-containing side chain. IV. Physicochemical and biological properties of the four diastereoisomers of 3 alpha,7 beta-dihydroxy-22,23-methylene-5 beta-cholan-24-oic acid
A Roda, B Grigolo, R Aldini, P Simoni, R Pellicciari, B Natalini and R Balducci
Istituto di Scienze Chimiche, Facolta di Farmacia, Universita degli Studi di Bologna, Italy.
To define the influence of the side chain modification on physicochemical
and biological properties of bile acids, 3 alpha,7 beta-
dihydroxy-22,23-methylene-5 beta-cholan-24-oic acid, a cyclopropyl analog
of ursodeoxycholic acid (UDCA) was synthesized in both unconjugated and
taurine-conjugated form. The presence of a cyclopropyl ring at C-22, C-23
position introduces chirality generating four diasteroisomers (A, B, C, and
D) which greatly differ for the hydrophilicity and critical micellar
concentration: A and B are more hydrophilic (K' = 0.21, 0.80 and CMC =
25,20 mM, respectively) than UDCA (K' = 0.95; CMC = 19 mM) while C and D
are more hydrophobic and with lower CMC (K' = 1.30, 2.05; CMC = 14, 10 mM,
respectively) than UDCA. Differences in these properties are related to the
orientation of the C-25 carboxyl which in isomers A and B is oriented
toward the back of the steroid body, reducing the continuity of the
hydrophobic area. Using the isolated perfused rat liver we found that the
isomers inhibited [3H]UDCA uptake differently. Isomer D (noncompetitive)
was the most potent (51%) while isomer A (competitive) was the least potent
(15%). When infused intravenously to rats, only D isomer and UDCA were
quantitatively recovered in bile. They were secreted predominantly as
taurine and glycine conjugates. Isomers A, B, C are not conjugated and only
partially recovered in bile as unconjugates (less than 15% of the
administered dose). The increase in bile flow per unit increase in bile
acid secretion induced by isomers A, B, and C, was much greater than that
induced by isomer D which is similar to that of UDCA (0.32 +/- 0.04 and
0.22 +/- 0.01, respectively) while it is reduced during infusion of the
other isomers. When infused as taurine conjugates they behaved similarly to
tauroursodeoxycholic acid. When incubated in anaerobic conditions with
human stools only isomer D is partially 7- dehydroxylated (t/2 = 18 hr)
even though slower than UDCA (t/2 = 5 hr). The substrate specificity of the
taurine conjugated toward cholyglycine hydrolase is very poor, only isomers
C and D are partially deconjugated with a kinetics much slower than that of
UDCA (10 hr vs. 0.2 hr). By using molecular models it is possible to
explain these differences due to the conformation of the side chain that,
in the case of isomer D, is quite similar to UDCA. These data are useful to
explain the metabolism of dihydroxy bile acids and to design new analogs
with enhanced cholelitholytic activity.
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