title: Influence of conformation and intramolecular hydrogen bonding on the acyl glucuronidation and biliary excretion of acetylenic bis-dipyrrinones related to bilirubin.
abstract: 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.
authors.affiliation: Division of Gastroenterology, University of California, San Francisco, California 94143-0538, USA. tony.mcdonagh@ucsf.edu
authors.forename: Antony F
authors.initials: AF
authors.lastname: McDonagh
authors.forename: David A
authors.initials: DA
authors.lastname: Lightner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001663:Bilirubin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics; D006860:Hydrogen Bonding; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000480:Alkynes; D020719:Glucuronides; D014453:Glucuronosyltransferase; D001663:Bilirubin