EFFECT OF SIDE-CHAIN LENGTH ON BIOTRANSFORMATION, HEPATIC TRANSPORT, AND CHOLERETIC PROPERTIES OF CHENODEOXYCHOLYL HOMOLOGS IN THE RODENT -STUDIES WITH DINORCHENODEOXYCHOLIC ACID, NORCHENODEOXYCHOLIC ACID, AND CHENODEOXYCHOLIC ACID

To assess the effect of side chain length on the metabolism and physio logical effects of homologues of chenodeoxycholic acid (CDCA), dinorCD CA, the C-22 homologue, was synthesized and its hepatic biotransformat ion, transport kinetics, and choleretic properties were defined In rat and hamster biliary fistula and in isolated perfused rat liver. Resul ts were compared with those of norCDCA, the C-23 homologue, and of CDC A, the natural C-24 homologue. In the rat, dinorCDCA was secreted most ly in unconjugated form (the majority as dinor-alpha-muricholic acid); the remainder was glucuronidated. In the hamster, glucuronidation was greater, and the unconjugated fraction contained equal parts of dinor CDCA and 5 beta-hydroxy-dinorCDCA. NorCDCA was glucuronidated extensiv ely (70%, rat; 40%, hamster), CDCA, in contrast, was efficiently amida ted with taurine or glycine. In the perfused liver, the initial uptake Yale of all three homologues was identical; later, regurgitation and/ or cholehepatic shunting of dinorCDCA and norCDCA, but not of CDCA, oc curred, In rats and hamsters with biliary fistulas, dinorCDCA and norC DCA, but not CDCA, induced a bicarbonate-rich hypercholeresis of canal icular origin, Hypercholeresis was not induced by the taurine conjugat e of dinorCDCA. Hepatobiliary retention of both dinorCDCA and norCDCA occurred, consistent with efficient ductular absorption (calculated to be 94%) and cholehepatic cycling of the unmetabolized bile acids, It is concluded that dinorCDCA, as norCDCA, is inefficiently amidated, is metabolized as a xenobiotic, and induces hypercholeresis. DinorCDCA i s the first dihydroxy bile acid to be identified that is secreted larg ely in unconjugated form in bile.