Effect of side chain length on biotransformation, hepatic transport, and choleretic properties of chenodeoxycholyl homologues in the rodent: Studies with dinorchenodeoxycholic acid, norchenodeoxycholic acid, and chenodeoxycholic acid
✍ Scribed by H Yeh; C D Schteingart; L R Hagey; H Ton-Nu; U Bolder; M A Gavrilkina; J H Steinbach; A F Hofmann
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 338 KB
- Volume
- 26
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
canalicular origin. Hypercholeresis was not induced by the
To assess the effect of side chain length on the metabolism taurine conjugate of dinorCDCA. Hepatobiliary retention of and physiological effects of homologues of chenodeoxycholic both dinorCDCA and norCDCA occurred, consistent with acid (CDCA), dinorCDCA, the C 22 homologue, was syntheefficient ductular absorption (calculated to be 94%) and chosized and its hepatic biotransformation, transport kinetics, lehepatic cycling of the unmetabolized bile acids. It is conand choleretic properties were defined in rat and hamster cluded that dinorCDCA, as norCDCA, is inefficiently amibiliary fistula and in isolated perfused rat liver. Results were dated, is metabolized as a xenobiotic, and induces compared with those of norCDCA, the C 23 homologue, and hypercholeresis. DinorCDCA is the first dihydroxy bile acid of CDCA, the natural C 24 homologue. In the rat, dinorCDCA to be identified that is secreted largely in unconjugated form was secreted mostly in unconjugated form (the majority as in bile. (HEPATOLOGY 1997;26:374-385.) dinor-a-muricholic acid); the remainder was glucuronidated. In the hamster, glucuronidation was greater, and the unconju-A previous report from this laboratory described improved gated fraction contained equal parts of dinorCDCA and 5bsynthesis of the C 23 (C-24-nor) derivatives of several of the hydroxy-dinorCDCA. NorCDCA was glucuronidated extenmost common natural bile acids 1 ; such compounds differ from sively (70%, rat; 40%, hamster). CDCA, in contrast, was the natural C 24 bile acids in having one less methylene group efficiently amidated with taurine or glycine. In the perfused in the side chain. Subsequent studies characterized the hepatic liver, the initial uptake rate of all three homologues was identibiotransformation and physiological properties of these nor bile cal; later, regurgitation and/or cholehepatic shunting of dinoracids when they are administered parenterally to the anesthe-CDCA and norCDCA, but not of CDCA, occurred. In rats tized rodent with biliary fistula 2-4 or infused into the isolated and hamsters with biliary fistulas, dinorCDCA and norCDCA, perfused rat 3,5,6 or hamster 5 liver. Norcholic acid, a trihydroxy but not CDCA, induced a bicarbonate-rich hypercholeresis of bile acid, was shown in the rat to be transported through the hepatocyte and secreted into bile without undergoing biotransformation, 2 in agreement with older studies [7][8][9] ; in contrast, cho-Abbreviations: CMC, critical micellar concentration; UDCA, ursodeoxycholic acid; CDCA, chenodeoxycholic acid; CoA, conenzyme A; IPRL, isolated perfused rat liver; lic acid was efficiently conjugated with taurine. 2 Norcholic acid HPLC, high-performance liquid chromatography; GC/MS, gas chromatography/mass induced a greater choleresis than cholic acid, an effect attributspectometry; ACA, apparent choleratic activity. able to its higher critical micellization concentration (CMC). 10