Glucuronidation and transporter-mediated efflux into bile are important in the elimination of xeno- and endobiotics, including the natural biladienone pigment bilirubin. The mechanisms of these processes and the structural factors that dictate whether cholephilic compounds are excreted directly in bile or require prior glucuronidation are poorly understood. To investigate effects of molecular shape and intramolecular hydrogen bonding on the interplay between direct excretion and glucuronidation in the liver, we studied a series of novel synthetic exploded and homologated bilirubin analogues. These include dicarboxylic mono- and diacetylenic tetrapyrroles with linear shapes that are unable to adopt the folded ridge-tile conformations that are crucially important in bilirubin metabolism. Intramolecular hydrogen bonding was varied by adjusting the alkyl chain lengths of the pendent carboxyl groups, and preferred conformations were predicted by molecular dynamics calculations. Metabolism studies were done in rats, including Gunn rats, congenitally deficient in UGT1 glucuronosyl tranferases, and TR- rats, deficient in the canalicular transporter Mrp2 (Abcc2). The results show strikingly that minor, seemingly inconsequential, changes in constitution, amplified by their influence on hydrogen bonding and molecular conformation, can profoundly influence competing clearance pathways in the liver, an effect that is unlikely to be restricted to bis-dipyrrinone carboxylic acids. Exposed carboxyl groups seem to favor the direct route of elimination, whereas the potential for carboxyl infolding by hydrogen bonding seems to favor glucuronidation. The results also show that molecular shape is less important in the hepatic glucuronidation and biliary excretion of bilirubin and of this series of acids than the capacity for intramolecular hydrogen bonding.
A new class of highly fluorescent (phi(F) 0.3-0.8) low molecular weight water-soluble cholephilic compounds has been synthesized in two steps from dipyrrinones. The dipyrrinone nitrogens are first bridged by reaction with 1,1'-carbonyldiimidazole to form an N,N'-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidine-3,5-dione) nucleus, and a sulfonic acid group is then introduced at C(8) by reaction with concd H(2)SO(4). The resulting sulfonated N,N'-carbonyl-bridged dipyrrinones ("sulfoglows") are isolated as their sodium salts. When the alkyl substituents of the lactam ring are lengthened from ethyl to decyl, sulfoglows become increasingly lipophilic while maintaining water solubility. Low molecular weight sulfoglows were rapidly excreted intact in both bile and urine after intravenous infusion into rats, but higher molecular weight sulfoglows were excreted more selectively in bile. Hepatobiliary excretion of sulfoglows was partially, but not completely, blocked in mutant rats deficient in the multidrug-resistance associated transport protein Mrp2 (ABCC2). These observations point to the feasibility of developing simple sulfoglows with clinical diagnostic potential that are normally excreted in bile but appear in urine when hepatic elimination is impaired by cholestatic liver disease.
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