Yeh H Z, Schteingart C D, Hagey L R, Ton-Nu H T, Bolder U, Gavrilkina M A, Steinbach J H, Hofmann A F
Department of Medicine, University of California San Diego, La Jolla 92093-0813, USA.
Hepatology. 1997 Aug;26(2):374-85. doi: 10.1002/hep.510260218.
To assess the effect of side chain length on the metabolism and physiological effects of homologues of chenodeoxycholic acid (CDCA), dinorCDCA, the C22 homologue, was synthesized and its hepatic biotransformation, transport kinetics, and choleretic properties were defined in rat and hamster biliary fistula and in isolated perfused rat liver. Results were compared with those of norCDCA, the C23 homologue, and of CDCA, the natural C24 homologue. In the rat, dinorCDCA was secreted mostly 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 dinorCDCA and 5beta-hydroxy-dinorCDCA. NorCDCA was glucuronidated extensively (70%, rat; 40%, hamster). CDCA, in contrast, was efficiently amidated with taurine or glycine. In the perfused liver, the initial uptake rate of all three homologues was identical; later, regurgitation and/or cholehepatic shunting of dinorCDCA and norCDCA, but not of CDCA, occurred. In rats and hamsters with biliary fistulas, dinorCDCA and norCDCA, but not CDCA, induced a bicarbonate-rich hypercholeresis of canalicular origin. Hypercholeresis was not induced by the taurine conjugate 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 is the first dihydroxy bile acid to be identified that is secreted largely in unconjugated form in bile.
为评估侧链长度对鹅去氧胆酸（CDCA）同系物代谢及生理效应的影响，合成了C22同系物二降CDCA，并在大鼠和仓鼠胆瘘模型以及离体灌注大鼠肝脏中确定了其肝脏生物转化、转运动力学和利胆特性。将结果与C23同系物去甲CDCA以及天然C24同系物CDCA的结果进行了比较。在大鼠中，二降CDCA大多以未结合形式分泌（大部分为二降α-鼠胆酸）；其余部分则与葡萄糖醛酸结合。在仓鼠中，葡萄糖醛酸结合程度更高，未结合部分中二降CDCA和5β-羟基-二降CDCA含量相等。去甲CDCA大量与葡萄糖醛酸结合（大鼠为70%；仓鼠为40%）。相比之下，CDCA能有效地与牛磺酸或甘氨酸酰胺化。在灌注肝脏中，所有三种同系物的初始摄取率相同；随后，二降CDCA和去甲CDCA出现反流和/或胆肝分流，但CDCA未出现。在有胆瘘的大鼠和仓鼠中，二降CDCA和去甲CDCA而非CDCA诱导了源自胆小管的富含碳酸氢盐的胆汁分泌增多。二降CDCA的牛磺酸共轭物未诱导胆汁分泌增多。二降CDCA和去甲CDCA均出现肝胆潴留，这与未代谢胆汁酸的高效胆小管吸收（计算为94%）和胆肝循环一致。结论是，二降CDCA与去甲CDCA一样，酰胺化效率低，作为外源性物质进行代谢，并诱导胆汁分泌增多。二降CDCA是首个被鉴定出在胆汁中主要以未结合形式分泌的二羟基胆汁酸。
