Xiaobo Zhong
University Of Kansas Medical Center
Project start date: 2010-02-01
Project end date: 2015-01-31
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Grants awarded to Xiaobo Zhong
IDENTIFICATION & FUNCTIONAL CHARACTERIZATION OF SNPS IN RXRA GENE
Xiaobo Zhong
University Of Kansas Medical Center, Msn 1039, Kansas City, Ks 66160
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genetic polymorphisms have been identified in drug-metabolizing enzyme genes of cytochrome-P450 (CYP) superfamily, such as CYP2D6, CYP2C9, and CYP2C19, which may help to explain significant differences in the metabolic rates for a variety of drugs. Such genetic polymorphisms have not been identified in CYP3A4 which is responsible for metabolizing more than 50% of prescription drugs. There is a critical need to elucidate the genetic polymorphisms that control variable gene expression and enzyme functions of this important protein. Gene expression of CYP3A4 is regulated at transcriptional level by a nuclear receptor mediated network, in which key transcriptional regulatory factors are nuclear receptors of pregnane-x-receptor (PXR), constitutive androstane receptor (CAR), and retinoid x receptor (RXR). Enzyme functions of CYP3A4 required a coenzyme, P450 oxidoreductase (POR), to provide electrons for oxidation reactions. The objective of this application is to determine the contribution of genetic polymorphisms in the PXR, CAR, RXRalpha, and POR genes to the manifestations of differential CYP3A4-mediated drug metabolic rates in liver. We propose to systematically exam functional influence of genetic polymorphisms in genes in the nuclear receptor mediated network on CYP3A4 gene expression and enzyme activity. The identification of genetic polymorphisms among these genes and to correlate these genetic polymorphisms with CYP3A4 enzyme activity, will provide a strong scientific foundation for further evaluation of inter-individual differences of drug metabolism for the 40% of prescription drugs metabolized by this enzyme
Keywords: C21 steroid; CP33; CP34; CPC9; CPCJ; CPD6; CRISP; CYP2C; CYP2C10; CYP2C19; CYP2C19 gene; CYP2C9; CYP2C9 gene; CYP2D; CYP2D6; CYP2D6 gene; CYP2DL1; CYP3; CYP3A; CYP3A13; CYP3A3; CYP3A4; CYP3A4 gene; CYPIIIA4; Coenzymes; Cofactors, Enzyme; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P-450; Cytochrome P-450 Enzyme System; Cytochrome P450; Dehydrogenases; Disease; Disorder; Drug Prescribing; Drug Prescriptions; Drugs; Electrons; Enzyme Gene; Enzymes; Evaluation; Foundations; Funding; Gene Expression; Genes; Genetic Polymorphism; Grant; HLP; Health; Individual Differences; Institution; Investigators; Liver; Mediating; Medication; Metabolic; NF-25; NIH; NR2B1; National Institutes of Health; National Institutes of Health (U.S.); Negative Beta Particle; Negatrons; Nuclear Receptors; Oxidoreductase; Oxidoreductase Gene; P450; P450 MP-4; P450 PB-1; P450-DB1; P450-PCN1; P450C2C; P450C2D; P450C3; P450IIC19; P450IIC9; P450PCN1; Pharmaceutic Preparations; Pharmaceutical Preparations; Polymorphism (Genetics); Polymorphism, Genetic; Pregnanes; Prescriptions, Drug; Proteins; RXRA; RXRA gene; Reaction; Receptor Protein; Reductases; Research; Research Personnel; Research Resources; Researchers; Resources; Retinoic Acid Agent; Retinoic Acid and Derivatives; Retinoids; Source; United States National Institutes of Health; body system, hepatic; coenzyme analog; constitutive androstane receptor; disease/disorder; drug metabolism; drug/agent; enzyme activity; gene product; organ system, hepatic; oxidation; polymorphism; pregnane compound; receptor
Project start date: 2009-05-01
Project end date: 2010-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2010
PFA/PA: RFA-RR-04-007
5P20RR021940-04_5680 (2009): $196694