In recent years, aldehyde oxidase (AO) has continued to grow as an important enzyme in drug metabolism. Herein, we have focused primarily on the inhibition kinetics of AO and also developing tools to better understand AO and its role in human biochemistry and drug metabolism. In the first study, we used a set of small molecule inhibitors to explore the impact of inhibitor structure on mode of inhibition. The results indicated that the mode of inhibition varied greatly with the choice of inhibitor, ranging from mostly uncompetitive to completely competitive Implications for mechanism of inhibition and potential drug-drug interactions in humans is discussed. In the second study, we looked at the impact that the substrate had on measuring inhibition profiles. When comparing one substrate, phthalazine, with another, N-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA), we saw a dramatic difference in inhibition mode. In every case, for a given inhibitor the measured mode of inhibition was much more competitive with DACA as the probe substrate. This translated to DDI prediction that varied based on the substrate that was used. Finally, we also developed and employed a trypsin digest and subsequent liquid chromatography tandem mass spectrometry analysis to determine absolute abundance of AO in human liver cytosol. We discussed the future impact of this method for the development of drug metabolism models and understanding the biochemical role of this enzyme.
|Advisor:||Jones, Jeffrey P.|
|Commitee:||Berkman, Clifford, Gloss, Lisa, Kang, ChulHee|
|School:||Washington State University|
|School Location:||United States -- Washington|
|Source:||DAI-B 75/05(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Organic chemistry|
|Keywords:||Aldehyde oxidase, Drug metabolism, Drug-drug interactions|
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