Metabolism of 7 beta-alkyl chenodeoxycholic acid analogs and their effect on cholesterol metabolism in hamsters.
The metabolism of 7-ethyl- and 7-propyl-chenodeoxycholic acids was studied in hamsters. Both bile acid analogs were absorbed efficiently by the intestine and secreted into the bile at rates similar to those of chenodeoxycholic acid. After intraduodenal administration into bile fistula hamsters, the 7-alkyl analogs were present in bile as the glycine and taurine conjugates. The glycine/taurine ratios were: chenodeoxycholic acid, 1.9; 7-ethyl analog, 0.3; and 7-propyl analog, 0.2. After oral administration, during a 21-day feeding experiment, the 14C-labeled analogs were recovered quantitatively in the feces. Chenodeoxycholic acid was largely 7-dehydroxylated to lithocholic acid in the intestinal tract. In contrast, the 7 alpha-hydroxy group of the 7-alkyl bile acids was completely resistant to bacterial action. 7-Ethyl-chenodeoxycholic acid was transformed in part to a compound tentatively identified as 7 alpha-hydroxy-3-oxo- 7 beta-ethyl-5 beta-cholanoic acid while 7-propyl-chenodeoxycholic acid was excreted unchanged. In the hamsters used, the 7-alkyl bile acid analogs did not inhibit the bacterial dehydroxylation of chenodeoxycholic acid. At the end of the 21-day feeding period, analysis of the gallbladder bile showed that 7-methyl-, 7-ethyl-, and 7-propyl-chenodeoxycholic acids accounted for 38, 31, and 12% of total bile acids, respectively. The 7-alkyl bile acids decreased cholesterol absorption; the 7-propyl analog caused significant decrease in serum and liver cholesterol concentration. These experiments demonstrate that the 7-ethyl- and 7-propyl chenodeoxycholic acids, just like the 7-methyl-analog, are absorbed by the intestine and participate in the enterohepatic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Une
M
M
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
Yamanaga
K
K
Mosbach
E H
EH
Tsujimura
K
K
Hoshita
T
T
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001711:Biotransformation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D005243:Feces / Q000032:analysis; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; C060839:3,7-dihydroxy-7-ethylcholanoic acid; C060838:3,7-dihydroxy-7-n-propylcholanoic acid; D014580:Ursodeoxycholic Acid; D002784:Cholesterol