A5090421334- Pharmacogenetics and Drug Metabolism
- Prostate Cancer Treatment and Research
- Hormonal and reproductive studies
- Estrogen and related hormone effects
- Cancer therapeutics and mechanisms
- Neonatal Health and Biochemistry
- Drug Transport and Resistance Mechanisms
- Biochemical and Molecular Research
- Prostate Cancer Diagnosis and Treatment
- Sexual Differentiation and Disorders
- Cancer, Hypoxia, and Metabolism
- Glutathione Transferases and Polymorphisms
- Chronic Lymphocytic Leukemia Research
- Renal Transplantation Outcomes and Treatments
- HIV/AIDS drug development and treatment
- Colorectal Cancer Treatments and Studies
- Cancer, Lipids, and Metabolism
- Nutritional Studies and Diet
- Acute Lymphoblastic Leukemia research
- Sperm and Testicular Function
- Endometrial and Cervical Cancer Treatments
- DNA Repair Mechanisms
- Glycosylation and Glycoproteins Research
- Metabolomics and Mass Spectrometry Studies
- Pancreatic and Hepatic Oncology Research
Centre hospitalier de l'Université Laval
2012-2025
Université Laval
2016-2025
Centre hospitalier universitaire de Québec
2016-2025
University of North Carolina at Chapel Hill
2013-2019
Division of Cancer Epidemiology and Genetics
2019
New York University
2019
National Cancer Institute
2019
University of Tübingen
2015-2019
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
2015-2019
Quebec Research and Development Centre
2019
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation atazanavir. Risk for bilirubin‐related is highest among individuals who carry two UGT1A1 decreased function alleles ( UGT1A1*28 or *37 ). We summarize published literature that supports this association provide...
7-Ethyl-10-hydroxycamptothecin (SN-38) is the pharmacologically active metabolite of irinotecan, in addition to being responsible for severe toxicity. Glucuronidation main metabolic pathway SN-38 and has been shown protect against irinotecan-induced gastrointestinal The purpose this study was determine whether common polymorphic UDP-glucuronosyltransferase (UGT) affects glucuronidation. First, kinetic characterization SN-38-glucuronide (SN-38-G) formation assessed all known human UGT1A UGT2B...
Mycophenolic acid (MPA), a standard immunosuppressive drug, is characterized by unexplained highly variable pharmacokinetics in transplant recipients. The primary metabolic pathway of MPA glucuronidation; however, literature reports are inconsistent and the contribution all human UDP-glucuronosyltransferases (UGTs) has never been systematically assessed. Sixteen heterologously expressed UGTs were studied for 7-<i>O</i>-glucuronidation compared with liver, kidney, intestine microsomes. For...
Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), most abundant circulating estrogen conjugates. The identity conjugated formed by all known overexpressed UGTs (n = 16) was analyzed comparison with retention time mass fragmentation authentic standards HPLC tandem spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, 2B7, were found glucuronidate estradiol (E2) estrone (E1), their hydroxyls (OH), methoxy...
Objectives Polymorphisms in UDP-glucuronosyltransferases (UGTs) can influence detoxifying capacities and have considerable therapeutic implications addition to various (patho)physiological processes. UGT1A9 plays a central role the metabolism of classes drugs carcinogens steroids. The great interindividual variability UGT1A9-mediated glucuronidation remains poorly explained, while evidence for its genetic origin exists. Methods proximal promoter was screened polymorphisms by sequencing and,...
In vitro metabolic studies revealed that along with UDP-glucuronosyltransferase (UGT) 1A1, the hepatic UGT1A9 and extrahepatic UGT1A7 are involved in biotransformation of active toxic metabolite irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38). Variant UGT1A1 alleles have been reported but polymorphic nature <i>UGT1A9</i> gene has not yet. To further clarify molecular determinants irinotecan-induced toxicity, we identified characterized functionality novel polymorphisms determined whether...
We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, enzymes producing phenolic (MPAG) acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to interindividual variation observed mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no (controls) carriers UGT1A9 —275/–2152 selected among 305 individuals genetically screened for UDP-glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups...
Glucuronidation by uridine diphospho-glucuronosyltransferase enzymes (UGTs) is a major phase II biotransformation pathway and, complementary to I metabolism and membrane transport, one of the most important cellular defense mechanisms responsible for inactivation therapeutic drugs, other xenobiotics, endogenous molecules. Interindividual variability in UGT pathways significant may have profound pharmacological toxicological implications. Several genetic genomic processes underlie this are...
Human pluripotent stem cells (hPSCs) represent a novel source of hepatocytes for drug metabolism studies and cell-based therapy the treatment liver diseases. These applications are, however, dependent on ability to generate mature metabolically functional from hPSCs. Reproducible efficient generation such has been challenging date, owing fact that regulatory pathways control hepatocyte maturation are poorly understood. Here, we show combination three-dimensional cell aggregation cAMP...
The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is directly conjugated by the UDP-glucuronosyltransferase (UGT) pathway to form EFV-<i>N</i>-glucuronide (EFV-G), but enzyme(s) involved has not yet been identified. glucuronidation of EFV was screened with UGT1A and UGT2B enzymes expressed in a heterologous system, UGT2B7 shown be only reactive enzyme. apparent <i>K</i><sub>m</sub> value (21 μM) similar observed for human liver microsomes (24 μM), whereas variant allozyme...
// Zhi-Qiang Wang 1, 2 , Adnen Faddaoui Magdalena Bachvarova Marie Plante 2, 3 Jean Gregoire Marie-Claude Renaud Alexandra Sebastianelli Chantal Guillemette 4, 5 Stéphane Gobeil 4 Elizabeth Macdonald 6 Barbara Vanderhyden Dimcho Bachvarov 1 Department of Molecular Medicine, Laval University, Québec PQ, Canada Centre de recherche du CHU Québec, L’Hôtel-Dieu Obstetrics and Gynecology, CHUL, Faculty Pharmacy, Cellular University Ottawa, ON, Correspondence to:...
Just as the androgen receptor (AR), estrogen α (ERα) is expressed in prostate and thought to influence cancer (PCa) biology. Yet, incomplete understanding of ERα functions PCa hinders our ability fully comprehend its clinical relevance restricts repurposing estrogen-targeted therapies for treatment this disease. Using two human tissue microarray cohorts, we first demonstrated that nuclear expression was heterogeneous among patients, being only detected half tumors. Positive levels were...
Glucuronidation is a crucial pathway for the metabolism and detoxification of drugs endobiotics, primarily occurs in liver. UGT2B17 one 22 glycosyltransferases (UGT) that catalyze this reaction. In large proportion population, absent due to complete gene deletion. We hypothesized human deficiency affects composition function liver proteome, potentially provoking compensatory responses, altering interconnected pathways regulatory networks. The objective was elucidate proteome...
One of the most important mechanisms involved in host defense against xenobiotic chemicals and endogenous toxins is glucuronidation catalysed by UDP-glucuronosyltransferase enzymes (UGT). The role genetic factors determining variable rates not well understood, but phenotypic evidence support such variation has been reported. In present study, six single nucleotide polymorphisms were discovered first exon UGT1A7 gene, which codes for putative substrate-binding domain, revealing a high...
(<i>R</i>,<i>S</i>)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that metabolized primarily by hepatic glucuronidation. In previous studies, <i>S</i>-oxazepam (but not <i>R</i>-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study identify UDP-glucuronosyltransferase (UGT) isoforms mediating <i>R</i>- and glucuronidation human liver, with long term objective elucidating molecular genetic basis for this metabolism polymorphism. All available...
Background: UDP-glucuronosyltransferase 1A7 (UGT1A7) detoxifies several tobacco carcinogens. We determined whether UGT1A7 expression is observed in normal orolaryngeal tissue and allelic variations are associated with the risk for cancer. Methods: was by semiquantitative reverse transcription–polymerase chain reaction (PCR). Buccal cell DNA isolated from 194 case subjects cancer 388 control who were matched sex, age, race subjected to genotyping use of combined PCR–restriction fragment...
To clarify the molecular determinants of metabolic variability morphine, we searched for genetic polymorphisms in gene uridine diphosphate–glucuronosyltransferase 2B7 ( UGT2B7 ) and evaluated their functional impact vitro patients with cancer receiving long‐term morphine therapy. Genetic analysis revealed existence 8 single‐nucleotide (SNPs), 6 which are tightly linked at positions −1248, −1241, −1054, −842, −268, −102 relative to hepatic start site. In contrast, an SNP position −66 occurs...
Renal metabolism by UDP-glucuronosyltransferase (UGT) enzymes is central to the clearance of many drugs. However, significant discrepancies about relative abundance and activity individual UGT in normal kidney prevail among reports, whereas glucuronidation tumoral has not been examined. In this study, we performed an extensive profiling (<i>n</i> = 12) tumor 14) kidneys using targeted mass spectrometry quantification human UGTs. We then correlated protein concentrations with mRNA levels...