McDonagh Antony F, Boiadjiev Stefan E, Lightner David A
Division of Gastroenterology and The Liver Center, Room S-357, Box 0538, University of California San Francisco, San Francisco, CA 94143-0538, USA.
Drug Metab Dispos. 2008 May;36(5):930-6. doi: 10.1124/dmd.107.019778. Epub 2008 Feb 25.
The hepatobiliary metabolism and excretion of three isomeric bilirubin analogs with propanoic replaced by benzoic acid side-chains were studied in the rat. Despite their isomeric relationship and similar constitutions, the three analogs were metabolized quite differently from each other and from bilirubin. In the di-o-benzoic compound, steric hindrance involving the phenyl groups reinforces intramolecular hydrogen bonding of the two carboxyl groups. This compound is considerably less polar than bilirubin on reverse-phase high-performance liquid chromatography and, like bilirubin, was not excreted in bile in UGT1-deficient (Gunn) rats. But, quite unlike bilirubin, it was not glucuronidated or excreted in bile in normal rats. In contrast to both bilirubin and the di-o-benzoic isomer, the more polar m- and p-isomers, in which intramolecular hydrogen bonding of carboxyl groups is sterically difficult, were excreted rapidly in bile in unchanged form in both normal and Gunn rats. However, only one of them, the di-m-isomer, was excreted rapidly and unchanged in bile in rats (TR(-) rats) congenitally deficient in the canalicular ATP-binding cassette transporter Mrp2. The marked differences in hepatobiliary metabolism of the three isomers studied can be rationalized on the basis of their computed three-dimensional structures and minimum-energy conformations and the remote effects of steric compression on intramolecular hydrogen bonding.
在大鼠中研究了三种苯环取代丙酸侧链的胆红素异构体类似物的肝胆代谢和排泄情况。尽管这三种类似物具有异构体关系且结构相似，但它们彼此之间以及与胆红素的代谢方式却有很大不同。在二邻苯甲酸化合物中，涉及苯基的空间位阻增强了两个羧基的分子内氢键作用。在反相高效液相色谱中，该化合物的极性比胆红素小得多，并且与胆红素一样，在缺乏UGT1的（Gunn）大鼠胆汁中不排泄。但是，与胆红素截然不同的是，它在正常大鼠中不会进行葡萄糖醛酸化或在胆汁中排泄。与胆红素和二邻苯甲酸异构体不同，极性更强的间位和对位异构体由于羧基的分子内氢键在空间上难以形成，在正常大鼠和Gunn大鼠中均以未改变的形式迅速排泄到胆汁中。然而，其中只有一种，即二间位异构体，在先天性缺乏胆小管ATP结合盒转运蛋白Mrp2的大鼠（TR（-）大鼠）胆汁中迅速且以未改变的形式排泄。所研究的三种异构体在肝胆代谢方面的显著差异，可以根据它们计算出的三维结构、最低能量构象以及空间压缩对分子内氢键的远程影响来解释。
