Journal of Lipid Research, Vol 30, 1005-1014, Copyright © 1989 by Lipid Research, Inc.
Synthesis of new bile acid analogues and their metabolism in the hamster: 3 alpha, 6 alpha-dihydroxy-6 beta-methyl-5 beta-cholanoic acid and 3 alpha, 6 beta-dihydroxy-6 alpha-methyl-5 beta-cholanoic acid
N Matoba, EH Mosbach, BI Cohen, M Une and CK McSherry
Department of Surgery, Beth Israel Medical Center, New York, NY 10003.
This paper reports the chemical synthesis of two new bile acid analogues,
namely, 3 alpha, 6 beta-dihydroxy-6 alpha-methyl-5 beta- cholanoic acid
from 3 alpha-hydroxy-6-oxo-5 beta-cholanoic acid and describes their
metabolism in the hamster. A Grignard reaction of the oxo acid with methyl
magnesium iodide in tetrahydrofuran gave two epimeric
dihydroxy-6-methyl-cholanoic acids which were separated as the methyl
esters by silica gel column chromatography. The configuration of the
6-methyl groups was assigned by proton nuclear magnetic resonance
spectroscopy and was supported by the chromatographic properties of the new
compounds. The metabolism of the two new bile acid analogues was studied in
the hamster. After intraduodenal administration of the 14C- labeled
analogues into bile fistula hamsters, both compounds were absorbed rapidly
from the intestine and secreted into bile. Intravenous infusion studies
revealed that these compounds were efficiently extracted by the liver; the
administered analogues became major biliary bile acids, present as either
the glycine or taurine conjugates. These compounds are useful to study the
effect of methyl-substituted bile acids on cholesterol and bile acid
metabolism and may possibly possess cholelitholytic properties.
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