BIOMAT Database Logo BIOMAT Database Logo

Novel inhibitors and substrates of bilirubin: UDP-glucuronosyltransferase. Arylalkylcarboxylic acids. 1989

S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Centre du Médicament, Unité de recherche associée 597, Centre National de la Recherche Scientifique, Nancy, France.

The in vitro inhibitory potency of 20 structurally related alkanoic and arylalkanoic acids has been investigated on rat liver UDP-glucuronosyltransferase. These compounds were tested on the microsomal and purified enzyme, and a cloned cDNA expressed in COS 7 cell cultures. Among all the acids tested, 7,7,7-triphenylheptanoic acid was the most powerful inhibitor of bilirubin:UDP-glucuronosyltransferase with a lower effect on 1-naphtol, androsterone and testosterone glucuronidation. The inhibition was competitive towards the microsomal and purified bilirubin:UDP-glucuronosyltransferases with Kiapp values of 12.0 microM and 1.6 microM, respectively. Twenty analogues were examined, and the results showed that their inhibitory potency on bilirubin:UDP-glucuronosyltransferase activity was a function of at least three structural features (a) the presence of a hydrophobic triphenyl moiety; (b) the length of the aliphatic chain and (c) the presence of a carboxylic group. These inhibitors were also tested as possible substrates of UDP-glucuronosyltransferases. The strongest inhibitors were poor substrates of rat liver microsomal UDP-glucuronosyltransferases. However, 7,7,7-triphenylheptanoic acid was actively glucuronidated by purified bilirubin:UDP-glucuronosyltransferase, in contrast to its analogues with decreasing alkyl chain length. In addition, glucuronidation of this molecule was enhanced by clofibrate treatment but could not be detected in Gunn rats, which are deficient in bilirubin:UDP-glucuronosyltransferase, further indicating that the glucuronidation of this compound was catalysed by bilirubin:UDP-glucuronosyltransferase. The results suggest that 7,7,7-triphenylheptanoic acid may be a useful structural probe to investigate the molecular basis of glucuronidation of bilirubin and carboxylic acids.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D002264 Carboxylic Acids Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. Carboxylic Acid,Acid, Carboxylic,Acids, Carboxylic
D002848 Chromatography, DEAE-Cellulose A type of ion exchange chromatography using diethylaminoethyl cellulose (DEAE-CELLULOSE) as a positively charged resin. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) DEAE-Cellulose Chromatography,Chromatography, DEAE Cellulose,DEAE Cellulose Chromatography
D006602 Hexosyltransferases Enzymes that catalyze the transfer of hexose groups. EC 2.4.1.-.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Substrates and products of purified rat liver bilirubin UDP-glucuronosyltransferase.
January 1986, Hepatology (Baltimore, Md.),
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Correlation between bilirubin glucuronidation and estradiol-3-gluronidation in the presence of model UDP-glucuronosyltransferase 1A1 substrates/inhibitors.
February 2011, Drug metabolism and disposition: the biological fate of chemicals,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
UDP-glucuronosyltransferase inhibitors.
January 1998, European journal of drug metabolism and pharmacokinetics,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Regulation of the human bilirubin UDP-glucuronosyltransferase gene.
January 1996, Advances in enzyme regulation,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
UDP-glucuronosyltransferase activity and bilirubin conjugation in the bullfrog.
May 1983, The Biochemical journal,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Bilirubin glucuronidation by intact Gunn rat fibroblasts expressing bilirubin UDP-glucuronosyltransferase.
March 1996, The Biochemical journal,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Natural and synthetic inhibitors of UDP-glucuronosyltransferase.
February 2001, Pharmacology & therapeutics,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Hepatic microsomal bilirubin UDP-glucuronosyltransferase. The kinetics of bilirubin mono- and diglucuronide synthesis.
August 1992, The Journal of biological chemistry,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism.
June 1999, Pediatrics,
S Fournel-Gigleux, and S R Shepherd, and M C Carre, and B Burchell, and G Siest, and P Caubere
Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol.
April 1993, Molecular pharmacology,
Copied contents to your clipboard!