Abstract
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.
Footnotes
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This work was supported by National Institutes of Health Grants HD-17779 and DK-26307.
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This work is dedicated to Professor Leslie Z. Benet on the occasion of his 70th birthday and to the memory of Professor Emeritus Rudi Schmid, who died on October 20, 2007, at the age of 85.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019778.
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ABBREVIATIONS: MRP2/Mrp2, multidrug resistance-associated protein 2; MeDocta, 0.1 M di-n-octylamine acetate in MeOH; TR-, Mrp2-deficient; HPLC, high-performance liquid chromatography.
- Received November 27, 2007.
- Accepted February 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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