Journal of Lipid Research, Vol 32, 1729-1740, Copyright © 1991 by Lipid Research, Inc.
Chemical synthesis and hepatic biotransformation of 3 alpha,7 alpha- dihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid, a 7-methyl derivative of norchenodeoxycholic acid: studies in the hamster
M Yoshii, EH Mosbach, CD Schteingart, LR Hagey, AF Hofmann, BI Cohen and CK McSherry
Department of Surgery, Beth Israel Medical Center, New York, NY 10003.
A new bile acid analogue, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-24- nor-5
beta-cholan-23-oic acid (7-Me-norCDCA) was synthesized from the methyl
ester of norursodeoxycholic acid, and its hepatic biotransformation was
defined in the hamster. To synthesize 7-Me- norCDCA, the 3 alpha-hydroxyl
group of methyl norursodeoxycholate was protected as the hemisuccinate, and
the 7 beta-hydroxyl group was oxidized with CrO3 to form the 7-ketone. A
Grigard reaction with methyl magnesium iodide followed by alkaline
hydrolysis gave 7-Me-norCDCA (greater than 70% yield). The structure of the
new compound was confirmed by proton magnetic resonance and mass
spectrometry. After intraduodenal administration of the 14C-labeled
compound into the anesthetized biliary fistula hamster, it was rapidly and
efficiently secreted into the bile; 80% of radioactivity was recovered in 2
h. After intravenous infusion, the compound was efficiently extracted by
the liver and secreted into the bile (greater than 75% in 3 h). Most (93%)
of the biliary radioactivity was present in biotransformation products. The
major biotransformation product (48.7 +/- 6.0%) was a new compound,
assigned the structure of 3 alpha,5 beta,7 alpha- trihydroxy- 7
beta-methyl-24-nor-5 beta-cholan-23-oic acid (5 beta-hydroxy-7- Me-
norCDCA). In addition, conjugates of 7-Me-norCDCA with taurine (13.7 +/-
5.0%), sulfate (10.3 +/- 3.0%), or glucuronide (5.1 +/- 1.7%) were formed.
7-Me-norCDCA was strongly choleretic in the hamster; during its intravenous
infusion, bile flow increased 2 to 3 times above the basal level, and the
calculated choleretic activity of the compound (and its metabolic products)
was much greater than that of many natural bile acids, indicating that the
compound induced hypercholeresis. It is concluded that the
biotransformation and physiological properties of 7- Me-norCDCA closely
resemble those of norCDCA. Based on previous studies, the major biological
effect of the 7-methyl group in 7-Me- norCDCA is to prevent its bacterial
7-dehydroxylation in the distal intestine.
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