Dissertation/Thesis Abstract

Altered UDP-glucuronosyltransferase regulation and expression: Implications for cancer cell proliferation and drug treatment
by Dates, Centdrika Renee', Ph.D., University of Arkansas for Medical Sciences, 2015, 147; 3703979
Abstract (Summary)

UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that are involved in the biotransformation of endogenous and exogenous compounds. This family of enzymes has been studied in detail in terms of detoxification; however, very little information is available in regards to the effects that altered expression and polymorphisms within the genes may have on cellular homeostasis. The purpose of the work presented in this thesis is to elucidate novel roles for UGTs in cancer and the metabolism of anti-cancer compounds, Tamoxifen (Tam) and its derivatives: 4-hydroxytamoxifen (4OHTam), Toremifene (Tor), and 4-hydroxytoremifene (4OHTor). First, I evaluated the effect of UGTs on cellular proliferation and lipids, which are substrates for UGTs. We hypothesized that exogenous re-introduction of the differentially expressed UGT2B isoforms would reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. Using molecular and biochemical methods, the effect of UGT2B4, 2B7, and 2B15 was analyzed. A significant decrease in cell proliferation, cellular lipid content, and an increase in the number of dead cells was seen with all 3 UGT isoforms in breast and pancreatic cell lines. Additionally, I investigated the effect of polymorphisms in the UGT1A family in the metabolism of Tam and its derivatives. We hypothesized that UGT1A4 promoter single nucleotide polymorphisms (SNPs) have the ability to decrease the glucuronidation rates of Tam metabolites and derivatives. In vitro assays using 64 genotyped human liver microsomes (HLMs) were used to determine the association between UGT1A4 promoter polymorphisms and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Decreases in enzymatic activity were observed in microsomes for individuals heterozygous for -163GUDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that are involved in the biotransformation of endogenous and exogenous compounds. This family of enzymes has been studied in detail in terms of detoxification; however, very little information is available in regards to the effects that altered expression and polymorphisms within the genes may have on cellular homeostasis. The purpose of the work presented in this thesis is to elucidate novel roles for UGTs in cancer and the metabolism of anti-cancer compounds, Tamoxifen (Tam) and its derivatives: 4-hydroxytamoxifen (4OHTam), Toremifene (Tor), and 4-hydroxytoremifene (4OHTor). First, I evaluated the effect of UGTs on cellular proliferation and lipids, which are substrates for UGTs. We hypothesized that exogenous re-introduction of the differentially expressed UGT2B isoforms would reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. Using molecular and biochemical methods, the effect of UGT2B4, 2B7, and 2B15 was analyzed. A significant decrease in cell proliferation, cellular lipid content, and an increase in the number of dead cells was seen with all 3 UGT isoforms in breast and pancreatic cell lines. Additionally, I investigated the effect of polymorphisms in the UGT1A family in the metabolism of Tam and its derivatives. We hypothesized that UGT1A4 promoter single nucleotide polymorphisms (SNPs) have the ability to decrease the glucuronidation rates of Tam metabolites and derivatives. In vitro assays using 64 genotyped human liver microsomes (HLMs) were used to determine the association between UGT1A4 promoter polymorphisms and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Decreases in enzymatic activity were observed in microsomes for individuals heterozygous for -163G

Indexing (document details)
Advisor: Radominska-Pandya, Anna
Commitee: Diekman, Alan, Haun, Randy, Kadlubar, Susan, Prather, Paul
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 76/09(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Oncology
Keywords: Breast cancer, Lipids, Pancreatic cancer, Single nucleotide polymorphisms, Tamoxifen, Ugts
Publication Number: 3703979
ISBN: 9781321761184
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