Structural and Functional Basis of Drug Binding to Human Cytochrome P450 2C9*14 Genetic Variant
Loading...
Issue Date
2022-12
Authors
Edara, Sreeja '22
Degree
MS in Pharmaceutical Sciences
Advisor
Shah, Manish
Committee Members
Lee, Insong James
Silvestro, Loraine
Silvestro, Loraine
Journal Title
Journal ISSN
Volume Title
Abstract
Cytochrome P450 (CYP) enzymes are a group of enzymes encoded by P450 genes and are expressed as membrane-bound proteins mostly found in the endoplasmic reticulum of the liver cells. About 17 of the 57 CYP proteins have a significant role in drug metabolism. CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are the major enzymes involved in drug metabolism. The highly polymorphic CYP2C9 is responsible for the metabolism of up to 15% of clinical drugs that include the anticoagulant S-Warfarin, the anti-hypertensive losartan, the anti-diabetic tolbutamide, and the analgesic ibuprofen, and others. The CYP2C9*14 allele, which results in the amino acid substitution from arginine to histidine at position 125 (R125H), is found in 3-5% of population, predominantly southeast Asians. Recent studies have illustrated that the CYP2C9*14 variant results in decreased enzyme function leading to the \342\200\234poor metabolizer\342\200\235 phenotype. For example, patients with this allele required a lower S-Warfarin dose compared to those with the normal or wild type allele. However, the implications of the CYP2C9*14 allele on the metabolism of losartan, an anti-hypertensive drug substrate of CYP2C9 is less clear. In this study, we aim to determine the impact of the amino acid change R125H (CYP2C9*14) on the binding of losartan using structural, functional, and biophysical analysis that include X-ray crystallography, enzymatic assays, and isothermal titration calorimetry, respectively. The results of this research will help advance our understanding of the effect of genetic polymorphisms and inter-individual differences in losartan response and may help implementing clinical guideline for patients on losartan that possesses the *14 allelic variation.
Citation
Edara S. Structural and functional basis of drug binding to human cytochrome p450 2c9*14 genetic variant [thesis]. Ann Arbor (MI): Proquest LLC; 2022. 62 p.
ACPHS Research Commons URI
Description
Click on the Resource Link to find this item in the ACPHS Library catalog.