Year of Award
2014
Document Type
Thesis
Degree Type
Master of Science (MS)
Degree Name
Pharmaceutical Sciences
Department or School/College
Department of Biomedical and Pharmaceutical Sciences
Committee Chair
Erica Woodahl
Commitee Members
Howard Beall, J. Stephen Lodmell, Keith Parker
Keywords
pharmacogenomics, pharmacogenetics, human liver microsomes, genotype-phenotype associations, genetic variability, CYP3A4 CYP3A5 linkage disequilibrium, Confederated Salish and Kootenai Tribes, lymphocytes
Publisher
University of Montana
Abstract
Researchers and clinicians are interested in how a patient’s individual genetic makeup could predict the appropriate medication and dose for that patient. One way to predict drug response, or efficacy, is by looking at enzymes within the liver that metabolize drugs. Many of these enzymes belong to a class called the Cytochrome P450s (CYPs). Specifically, two closely related enzymes, CYP3A4 and CYP3A5, are involved in metabolizing 50% of drugs currently on the market (eg: statins, antiepileptics, anticancer agents, and antidepressants). There can be differences in the genetic code of these enzymes that can causes changes in drug metabolism. We completed a study with participants from the Confederated Salish and Kootenai Tribes (CSKT), located on the Flathead Reservation in northwest Montana. Select CYP enzymes were genotyped, including CYP3A4 and CYP3A5. Most SNPs identified in the CSKT participants were found at frequencies similar to those reported in European-descended populations. Interestingly, one specific SNP, called CYP3A4*1G, was discovered at a high allele frequency. The physiological significance of this SNP is unclear as there are limited and confounding data, however, most of the data published to date suggest that the SNP causes decreased metabolism of drugs. Clinically, this could result in a need for a decreased dose of medication. In addition, this CYP3A4 SNP was observed to be often inherited with another SNP in the related CYP3A5 gene, called CYP3A5*3, which encodes a nonfunctional enzyme. These SNPs found in the CSKT are of particular interest, because inheriting these two SNPs together could cause drastic changes in drug metabolism since the two enzymes metabolize many of the same drugs.
Recommended Citation
Skagen, Kasse Jean, "Interindividual Variability in the Cytochrome P450 3A4 Drug Metabolizing Enzyme: Effect of the CYP3A4*1G Genetic Variant" (2014). Graduate Student Theses, Dissertations, & Professional Papers. 4351.
https://scholarworks.umt.edu/etd/4351
© Copyright 2014 Kasse Jean Skagen