This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Drug-drug interactions alter the in vitro and in vivo kinetics of cytochrome P450-mediated metabolism of single drugs and have the potential for reducing the efficacy of drug based therapy. Some cytochrome P450 isoforms demonstrate increased metabolism or atypical kinetics for the metabolism of certain substrates. We and others have suggested that simultaneous binding of two substrates in the active site (a two-site model) is responsible for most atypical kinetic profiles (e.g. dapsone and structurally related substrates activate CYP2C9 metabolism of flurbiprofen, naproxen, and piroxicam). The kinetic data suggest both substrate and activator are present in the active site. CYP2C9 polymorphisms have resulted in reduced enzyme catalytic activity and greater activation by effector molecules as compared to wild-type protein, with the mechanism(s) for these changes in activity not fully elucidated. We hypothesize that activators cause atypical kinetics by repositioning the substrate nearer the active site, increasing the probability of metabolism, and that this is caused by a combination of substrate-activator, substrate-active site, and activator-active site interactions that can be elucidated through a combination of molecular modeling and site-directed mutagenesis experiments. Selected mutations involving key sites that have been implicated in regulating catalytic activity will be studied by molecular modeling methods and correlated with the experimental kinetic data of these mutants. This comparison will determine if these key sites are responsible for the changes in activity between various mutants of CYP 2C9 and the likely causes of the altered kinetics. The kinetics for these mutations will be compared to these distance changes and correlations between the two studied. The mutants are R108I and N204I as they are responsible for substrate binding within the active site. Other mutants E300I, S209A, T304A, and N474I will be studied as they may determine binding orientation of the effector. This will provide information that will aid in the development of a model for predicting when substrate-effector combinations will cause atypical kinetics and provide an improved understanding of cytochrome P450 2C9 mediated metabolism.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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Marshall University
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Pan, Haibo; Wang, Fang; Rankin, Gary O et al. (2017) Inhibitory effect of black tea pigments, theaflavin?3/3'-gallate against cisplatin-resistant ovarian cancer cells by inducing apoptosis and G1 cell cycle arrest. Int J Oncol 51:1508-1520
Alway, Stephen E; Mohamed, Junaith S; Myers, Matthew J (2017) Mitochondria Initiate and Regulate Sarcopenia. Exerc Sport Sci Rev 45:58-69
Kocher, Caitlin; Christiansen, Matthew; Martin, Sarah et al. (2017) Sexual dimorphism in obesity-related genes in the epicardial fat during aging. J Physiol Biochem 73:215-224
Wang, Yaomin; Compton, Casey; Rankin, Gary O et al. (2017) 3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells. Int J Oncol 50:1392-1402
Jones, Brandon C; Kelley, Laura C; Loskutov, Yuriy V et al. (2017) Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior. Mol Cancer Res 15:670-682
Amos, Deborah L; Robinson, Tanner; Massie, Melissa B et al. (2017) Catalase overexpression modulates metabolic parameters in a new 'stress-less' leptin-deficient mouse model. Biochim Biophys Acta 1863:2293-2306
Haramizu, Satoshi; Asano, Shinichi; Butler, David C et al. (2017) Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts. J Nutr Biochem 50:103-115
He, Xiaoqing; Wang, Liying; Riedel, Heimo et al. (2017) Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer 16:63
Wang, Kai; Bruce, Allison; Mezan, Ryan et al. (2016) Nanotopographical Modulation of Cell Function through Nuclear Deformation. ACS Appl Mater Interfaces 8:5082-92
Moore, Ondrea A; Gao, Ying; Chen, Allen Y et al. (2016) The Extraction, Anticancer Effect, Bioavailability, and Nanotechnology of Baicalin. J Nutr Med Diet Care 2:

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