Biliary excretion of a stretched bilirubin in UGT1A1‐deficient (Gunn) and Mrp2‐deficient (TR⁻) rats

Abstract

The metabolism and biliary excretion of a stretched bilirubin analog with a p-xylyl group replacing the central CH 2 hinge were investigated in normal rats, Gunn rats deficient in bilirubin conjugation, and TR 3 rats deficient in bilirubin glucuronide hepatobiliary transport. Unlike bilirubin, the analog was excreted rapidly in bile unchanged in all three rat strains after intravenous administration. In TR 3 rats biliary excretion of the analog was diminished, but still substantial, demonstrating that the ATP-binding cassette transporter Mrp2 is not required for its hepatic efflux. These effects are attributable to differences in the preferred conformations of bilirubin and the analog. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Promotive Effects of the Dietary Organic Germanium Poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) on the Secretion and Antioxidative Activity of Bile in Rodents

“…The result for Ugt1a1 expression is in accord with the data for bilirubin glucuronide found by HPLC analysis of the bile juice of rats. Moreover, a detoxifying effect caused by the up-regulation of Ugt1a1 by Ge-132 intake is expected, 26,27) and the elevation of detoxicity after Ugt1a1 induction by dietary Ge-132 is also predicted.…”

“…25) Up-regulation of Ugt1a1 by Ge-132 may affect the detoxifying ability of the phase II detoxic system of the liver. 26,27) Bile juice is constantly being produced, and bilirubin is contained in it; therefore, the radical scavenging action of this molecule must be considerably strong.…”

Hepatic Metabolism and Biliary Excretion of Silymarin Flavonolignans in Isolated Perfused Rat Livers: Role of Multidrug Resistance-Associated Protein 2 (Abcc2)

“…The IPRL technique has been used successfully in various genetic animal models to investigate the precise mechanisms of hepatobiliary disposition of drugs. For example, a number of studies have employed IPRL to examine the role of Mrp2 utilizing TR - rats which are mutant rats that lack functional Mrp2 at the canalicular membrane (Jansen et al, 1985; McDonagh et al, 2001), similar to patients with Dubin-Johnson syndrome (Paulusma et al, 1997). Such studies have demonstrated marked reduction in biliary excretion of glucuronide and sulfate conjugates of drugs and other compounds in TR - rats, implying that Mrp2 is responsible for the biliary excretion of organic anions.…”

Slipping Past UGT1A1 and Multidrug Resistance-Associated Protein 2 in the Liver: Effects of Steric Compression and Hydrogen Bonding on the Hepatobiliary Elimination of Synthetic Bilirubins

“…Deficiencies of UGT1A1 cause neonatal jaundice, Gilbert's and CriglerNajjar syndromes (Kaplan and Hammerman, 2005), and congenital deficiency of MRP2 underlies the rare Dubin-Johnson syndrome (Nies and Keppler, 2007). Studies on bilirubin glucuronides led to the discovery that acyl glucuronides of many drugs are reactive, potentially toxic, metabolites (Smith et al, 1986), and studies on bilirubin analogs have revealed how subtle changes in molecular conformation can profoundly influence hepatic metabolism (McDonagh and Lightner, 1991;McDonagh et al, 2001;McDonagh and Lightner, 2007). Thus, although not generally considered drugs, bilirubins offer insight for the study of many aspects of drug metabolism.…”

“…Separating the dipyrromethenone chromophores by inserting spacers in place of the central C10 bridge, as in 3 and 4 (Fig 3), also leads to molecules that do not require phase-2 metabolism for facile biliary elimination (McDonagh et al, 2001;McDonagh and Lightner, 2007). And molecules, such as 5, that represent one half of a bilirubin molecule and do not contain NH/NHCO functions to which the lone COOH can reach are also eliminated largely unchanged in bile in the rat (McDonagh and Lightner, 1991).…”