The UDP-glucuronosyltransferases (UGTs) are a family of enzymes involved in the metabolism of many drugs and xenobiotic compounds, as well as endogenous compounds, such as bilirubin, steroid hormones, bile acids, and thyroid hormones. Information on one important class of physiological compounds, retinoid glucuronides, and the enzymes involved in the glucuronidation of retinoic acid and related retinoids is limited. Specifically, the identity of the UGTs that have specificity toward retinoids have not been identified. One of the principal goals of this proposal is to elucidate mechanisms of formation and the chemical structures of the retinoid glucuronides. Specifically, this work will critically test the hypothesis predicting the presence of retinoid UGT enzymes in hepatic microsomes. It is postulated that they are either entirely novel isoforms or among the existing UGTs with unidentified substrate specificity for retinoids. In order to investigate this hypothesis, the following specific aims are proposed: 1) characterize retinoid glucuronidating activity in rat liver microsomes; 2) identify and isolate retinoid UGT protein(s) from rat liver microsomal fractions; and 3) identify available or novel recombinant UGT isoenzymes for retinoid glucuronidation activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK051971-01A1
Application #
2402833
Study Section
Special Emphasis Panel (ZRG4-HEM-2 (02))
Program Officer
Akolkar, Beena
Project Start
1997-09-01
Project End
2001-07-31
Budget Start
1997-09-01
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Li, Xin; Bratton, Stacie; Radominska-Pandya, Anna (2007) Human UGT1A8 and UGT1A10 mRNA are expressed in primary human hepatocytes. Drug Metab Pharmacokinet 22:152-61
Xiong, Yan; Bernardi, Dan; Bratton, Stacie et al. (2006) Phenylalanine 90 and 93 are localized within the phenol binding site of human UDP-glucuronosyltransferase 1A10 as determined by photoaffinity labeling, mass spectrometry, and site-directed mutagenesis. Biochemistry 45:2322-32
Radominska-Pandya, Anna; Bratton, Stacie; Little, Joanna M (2005) A historical overview of the heterologous expression of mammalian UDP-glucuronosyltransferase isoforms over the past twenty years. Curr Drug Metab 6:141-60
Finel, Moshe; Li, Xin; Gardner-Stephen, Dione et al. (2005) Human UDP-glucuronosyltransferase 1A5: identification, expression, and activity. J Pharmacol Exp Ther 315:1143-9
Antonio, Laurence; Xu, Jing; Little, Joanna M et al. (2003) Glucuronidation of catechols by human hepatic, gastric, and intestinal microsomal UDP-glucuronosyltransferases (UGT) and recombinant UGT1A6, UGT1A9, and UGT2B7. Arch Biochem Biophys 411:251-61
Chen, Guangping; Zhang, Daqing; Jing, Nin et al. (2003) Human gastrointestinal sulfotransferases: identification and distribution. Toxicol Appl Pharmacol 187:186-97
Radominska-Pandya, Anna; Pokrovskaya, Irina D; Xu, Jing et al. (2002) Nuclear UDP-glucuronosyltransferases: identification of UGT2B7 and UGT1A6 in human liver nuclear membranes. Arch Biochem Biophys 399:37-48
Radominska-Pandya, Anna; Chen, Guangping (2002) Photoaffinity labeling of human retinoid X receptor beta (RXRbeta) with 9-cis-retinoic acid: identification of phytanic acid, docosahexaenoic acid, and lithocholic acid as ligands for RXRbeta. Biochemistry 41:4883-90
Radominska-Pandya, A; Little, J M; Czernik, P J (2001) Human UDP-glucuronosyltransferase 2B7. Curr Drug Metab 2:283-98
Jude, A R; Little, J M; Czernik, P J et al. (2001) Glucuronidation of linoleic acid diols by human microsomal and recombinant UDP-glucuronosyltransferases: identification of UGT2B7 as the major isoform involved. Arch Biochem Biophys 389:176-86

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