Professor

Ph.D., Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland

E-mailRadominskaAnna@uams.edu
Office:  (501)603-5414 – Barton 6R27A
Lab:  (501)603-1145 – Barton 6R27B
FAX:  (501)603-1146

Clinical and Pharmacological Roles of Human UDP-Glucuronosyltransferases

Structure-function relationship studies of human UDP-glucuronosyltransferases (UGTs).  Our laboratory is extensively involved in structure-function relationship studies of human UGTs.  UGTs are a class of enzymes that are involved in the detoxification of a variety of toxic and endogenous compounds.  Our goal is to identify critical amino acids within the active sites of these enzymes using photoaffinity labeling and crystallography.  For our studies we have available sufficient amounts of recombinant UGT protein expressed in baculovirus infected Sf9 insect cells.  In our photoaffinity experiments, we use UGT substrates or inhibitors that have been modified with a photolabile group, which upon photoactivation of this probe in situ covalently bind to the active site of the UGT protein.  Our probes have proven indispensable for the identification of both the co-substrate and substrate-binding sites of the UGTs.  We have generated the first comprehensive data in this area, identifying the phenol binding site of UGT1A10.  We also have fruitful collaborative studies that have led to the generation of the first partial crystal structure of any mammalian UGT (human UGT2B7).  Information generated from these studies will lead to the identification of more UGT binding sites and will eventually result in the elucidation of the molecular mechanisms of the important detoxification processes carried out by UGTs.  This information can then be directly applied to pharmacological and clinical settings, resulting in the design of safer and more efficient medications.

Role of human UGTs in cancer.   It is recognized that UGTs can metabolize a wide range of toxins and carcinogens and, therefore, play a critical role in detoxification of these compounds.  We also know that UGTs play an important role in conjugation anti-cancer drugs and endogenous lipids, as well as controlling the steady-state concentrations of ligands for nuclear receptors all of which are essential for driving the proliferation of cancer cells.  We and others have observed a correlation between the absence of UGT expression and cell proliferation. Comparisons of UGT expression levels in normal and cancer cells demonstrated a significant reduction in UGT mRNA in a number of tumor samples.  It is hypothesized that down regulation of UGTs could be one of the basic events in neoplastic transformation.  We have demonstrated that the levels of UGTs in cancer cells, as compared to corresponding normal cells, are significantly reduced or totally absent. Our study with ovarian cancer cells, which are lacking UGT2B7, demonstrated that stable expression of UGT2B7 in these cells resulted in colony formation, cell growth arrest, and decreased cell proliferation.  Similar studies are also being done with breast cancer tissue.  These data allows us to propose a role for UGTs in preventing hormone-induced and/or chemical carcinogenesis.

The role of UGTs and SULTs in the biotransformation of Drugs: Recently, we identified several drugs as novel substrates for human hepatic and extrahepatic UGTs and SULTs.

  • Warfarin:  We identified hydroxylated derivatives of warfarin as novel substrates for human hepatic and extrahepatic UGTs and SULTs in vitro. Then using metabolomics, we investigated the in vivo formation of glucuronidated and sulfated hydroxywarfarins in patients on warfarin therapy.
  • Synthetic Marijuana: We identified hydroxylated derivatives of the abused synthetic cannibinoids, JWH-018 and JWH-073, as novel substrates for human hepatic and extrahepatic UGTs and SULTs in vitro. Metabolomics was also used investigate the in vivo formation of glucuronidated JWH compound in urine collected from people suspected of abusing these drugs.  These studies have led to a validated method for using conjugated metabolites of these compounds as biomarkers for the determining whether a person had been using these illegal drugs.
  • Resveratrol Derivatives.  We have also identified several derivatives of the stilbinoid Resveratrol as novel substrates for human hepatic and extrahepatic UGTs.

Regulation of Human UGTs.  Our research in this area is focused on the transcriptional regulation of UGTs from the UGT1A and UGT2B families.  Our research builds on our findings that: 1) UGT1A isoforms are target genes for two human nuclear receptors, hPXR and hCAR. 2) UGT2B7, which glucuronidates a variety of endogenous compounds recognized as ligands for NRs, is down-regulated by bile acids and retinoic acid.  3) Two human isoforms from the UGT1A family, UGT1A3 and 1A4, are targets for AhR.  Characterization of the mechanism by which endogenous and exogenous compounds regulate UGT expression can lead to: 1) understanding of UGTs function in a normal state and in various diseases, such as cancer, and 2) it will also allow for the development of NR-targeted genes that will be able to increase or decrease UGTs activity.

Selected Publications

Fedejko-Kap B, Bratton SM, Finel M, Radominska-Pandya A, Mazerska Z. The Role of Human UDP-glucuronyltransferases in the Biotransformation of the Triazolo- and Imidazoacridinone Antitumor Agents C-1305 and C-131: Highly Selective Substrates for UGT1A10. Drug Metab Dispos. 2012 Jun 1. [Epub ahead of print] [Abstract]

Seely KA, Brents LK, Radominska-Pandya A, Endres GW, Keyes GS, Moran JH, Prather PL. A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors. Chem Res Toxicol. 2012 Apr 16;25(4):825-7. [Abstract]

Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, Moran JH, Prather PL. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol. 2012 Apr 1;83(7):952-61. [Abstract]

Bratton SM, Mosher CM, Khallouki F, Finel M, Court MH, Moran JH, Radominska-Pandya A. Analysis of R- and S-hydroxywarfarin glucuronidation catalyzed by human liver microsomes and recombinant UDP-glucuronosyltransferases. J Pharmacol Exp Ther. 2012 Jan;340(1):46-55. [Abstract]

Brents LK, Medina-Bolivar F, Seely KA, Nair V, Bratton SM, Nopo-Olazabal L, Patel RY, Liu H, Doerksen RJ, Prather PL, Radominska-Pandya A. Natural prenylated resveratrol analogs arachidin-1 and -3 demonstrate improved glucuronidation profiles and have affinity for cannabinoid receptors. Xenobiotica. 2012 Feb;42(2):139-56. [Abstract]

Fedejko-Kap B, Niemira M, Radominska-Pandya A, Mazerska Z. Flavin monooxygenases, FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to metabolism of anti-tumour triazoloacridinone, C-1305, in liver microsomes and HepG2 cells. Xenobiotica. 2011 Dec;41(12):1044-55. [Abstract]

Höglund C, Sneitz N, Radominska-Pandya A, Laakonen L, Finel M. Phenylalanine 93 of the human UGT1A10 plays a major role in the interactions of the enzyme with estrogens. Steroids. 2011 Dec 11;76(13):1465-73. [Abstract]

Chimalakonda KC, Bratton SM, Le VH, Yiew KH, Dineva A, Moran CL, James LP, Moran JH, Radominska-Pandya A. Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases. Drug Metab Dispos. 2011 Oct;39(10):1967-76. [Abstract]

Chimalakonda KC, Moran CL, Kennedy PD, Endres GW, Uzieblo A, Dobrowolski PJ, Fifer EK, Lapoint J, Nelson LS, Hoffman RS, James LP, Radominska-Pandya A, Moran JH. Solid-phase extraction and quantitative measurement of omega and omega-1 metabolites of JWH-018 and JWH-073 in human urine. Anal Chem. 2011 Aug 15;83(16):6381-8. [Abstract]

Karmakar A, Bratton SM, Dervishi E, Ghosh A, Mahmood M, Xu Y, Saeed LM, Mustafa T, Casciano D, Radominska-Pandya A, Biris AS. Ethylenediamine functionalized-single-walled nanotube (f-SWNT)-assisted in vitro delivery of the oncogene suppressor p53 gene to breast cancer MCF-7 cells. Int J Nanomedicine. 2011;6:1045-55. [Abstract]

Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH. Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem. 2011 Jun 1;83(11):4228-36. [Abstract]

Read a more comprehensive list of my publications.