Dissertation
TIME-DEPENDENT INHIBITION OF CYTOCHROME P450: INTEGRATING ADVANCED BIOPHYSICAL MEASUREMENTS INTO PREDICTIVE ANALYSES
Doctor of Philosophy (PhD), Washington State University
01/2016
Handle:
https://hdl.handle.net/2376/111964
Abstract
The implicit assumption made in extrapolating in vitro data to predict in vivo condition is that the qualitative behaviors of enzymes are for the most part independent of their external biochemical environments. However, cytochrome P450 superfamily (CYP), the enzyme responsible for the metabolism of drugs and xenobiotic, presents such a complex biochemical landscape that simplistic approaches usually lead to unreliable predictions. This is the case of time-dependent inhibition (TDI), which result in the inactivation of CYP over time, which is catalytically incompetent and needs to be replenished by newly synthetized protein. TDI kinetics are often characterized by mechanisms of metabolic intermediate complex (MIC) formation, shown for compounds containing amines or methylenedioxyphenyl (MDP) moieties.
At present, in vitro TDI analyses lack the resolution for quantitative prediction of clinical outcomes. The central hypothesis of this proposal is that understanding the factors that are important in TDI will allow us to predict when TDI will have the potential for clinical adverse reactions. Chapter 1 of this dissertation will provide a brief introduction to the mechanistic landscape of MICs formation as well as the rationale behind the numerical approach that our group developed. In Chapter 2 the emission spectroscopy of Cytochrome P450 will be characterized as a novel tool to determine binding affinities of several drugs in solution and lipid environments. Chapter 3 will explore the application of our numerical strategy to the TDI of CYP3A4 as mediated by podophyllotoxin, a drug containing a MDP moiety. In Chapter 4 we will further test the reliability of our method studying the inhibition of CYP2D6 by paroxetine, a potent serotonin inhibitor. Finally, in Chapter 5 we discuss the potential future directions in the study of cytochrome P450 time-dependent inhibition.
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Details
- Title
- TIME-DEPENDENT INHIBITION OF CYTOCHROME P450: INTEGRATING ADVANCED BIOPHYSICAL MEASUREMENTS INTO PREDICTIVE ANALYSES
- Creators
- Carlo Barnaba
- Contributors
- Jeffrey P Jones (Advisor)James A Brozik (Committee Member)ChulHee Kang (Committee Member)Kerry W Hipps (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Chemistry
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 142
- Identifiers
- 99900581632701842
- Language
- English
- Resource Type
- Dissertation