Hepatic uptake, transport and metabolism of alkylated bilirubins in Gunn rats and Sprague-Dawley rats.
We studied the metabolism and biliary excretion of four novel analogs of bilirubin in homozygous Gunn rats and Sprague-Dawley rats. All four compounds closely resemble bilirubin in constitutional structure but two of them contain strategically-placed geminal dimethyl substituents. These substituents destabilize, by steric buttressing, preferred ridge-tile conformational isomers and weaken intramolecular hydrogen bonding. The two analogs which lack geminal dimethyl substituents behaved like bilirubin itself--after intravenous administration they were metabolized to monoglucuronides and diglucuronides in Sprague-Dawley rats and not excreted significantly in bile in Gunn rats. The corresponding gem-dimethyl compounds--which, counter-intuitively, are much more polar than bilirubin--were, nevertheless, not excreted efficiently in bile Gunn rats. But, surprisingly, in Sprague-Dawley rats they were each metabolized predominantly to a single glucuronide metabolite, apparently a monoglucuronide. Thus, apparently minor constitutional changes, provoking subtle alterations of three-dimensional structure and hydrogen bonding, can have marked effects on the metabolism and hepatic processing of bilirubins in vivo.
Division of Gastroenterology, University of California, San Francisco 94143-0538.
A F
AF
McDonagh
D A
DA
Lightner
D000478:Alkylation; D000818:Animals; D001663:Bilirubin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D001693:Biological Transport, Active; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D011911:Rats, Gunn; D017207:Rats, Sprague-Dawley; D013816:Thermodynamics
D005965:Glucuronates; D001663:Bilirubin