Grazyna D. Szklarz, PhD

Associate Professor

Organization:

West Virginia University School of Pharmacy

Department:

Pharmaceutical Sciences

Classification:

Faculty

Member

Organization:

West Virginia University WVU Cancer Institute

Department:

WVU Cancer Institute Research Programs

Classification:

Faculty

• PhD, Clarkson University, 1991

Ten Most Recent:

Gálvez-Peralta M., Szklarz G., Geldenhuys, W., Lockman, P. An Effective Approach to Teaching Pharmacogenomics in the First Year of Pharmacy Curriculum.  Am. J. Pharm. Ed. Posted online on 1 Nov 2017.

Huo, L., Liu, J., Dearing, M.D., Szklarz, G.D, Halpert, J.R., and Wilderman, P.R. 2017. Rational Re-Engineering of the Oxidation of 7-Alkoxycoumarin Derivatives by Cytochromes P450 2B from the Desert Woodrat Neotoma lepida.  Biochemistry, 56:2238−2246. doi: 10.1021/acs.biochem.7b00097. Epub 2017 Apr 12. PMID: 28375626

Shah, M.B., Liu, J., Huo, L., Zhang, Q., Dearing, M.D., Wilderman, P.R., Szklarz, G.D., Stout, C.D., Halpert, J.R.. 2016. Structure-function analysis of mammalian CYP2B enzymes using 7-substituted coumarin derivatives as probes: Utility of crystal structures and molecular modeling in understanding xenobiotic metabolism. Mol Pharmacol. 89:435-445. doi: 10.1124/mol.115.102111. Epub 2016 Jan 29. PMID: 26826176 

Wang, L., He, X., Szklarz, G.D., Bi, Y., Rojanasakul, Y., and Ma, Q. 2013. The aryl hydrocarbon receptor interacts with nuclear factor erythroid 2-related factor 2 to mediate induction of NAD(P)H:quinone- oxidoreductase 1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Arch. Biochem. Biophys. 537:31–38. doi: 10.1016/j.abb.2013.06.001. Epub 2013 Jun 22. PMID: 23800876      

Walsh A.A., Szklarz G.D., Scott E.E. 2013. Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. J. Biol. Chem. 288:12932-12943.                                                

Trickett-Shockey, A.K., Wilson, C.S., Lander, L.R., Barretto, G.A., Szklarz, G.D., VanVoorhis, G.C.  and Minardi, J.J. 2013. The effect of rural upbringing and education on the intent of health professional students to work in rural settings. Int. J. Med. Educ. 4:18-25.                                                                        

Huang, Q., Deshmukh, R.S., Ericksen, S.S., Tu, Y. and Szklarz, G.D.  2012. Preferred binding orientations of phenacetin in CYP 1A1 and 1A2 are associated with isoform-selective metabolism. Drug Metab. Dispos. 40:  2324–2331.                                                                                                                            

He, X. Wang, L., Szklarz G, Bi, Y. and Ma, Q.  2012. Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the Nrf2 pathway. J. Pharmacol. Exp. Ther. 342: 81-90.    

Rademacher, P.M., Woods, C.M., Huang, Q., Szklarz, G.D. and Nelson, S.D. 2012. Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9. Chem. Res. Toxicol. 25: 895-903.

Huang, Q. and Szklarz, G.D. 2010. Significant increase in phenacetin oxidation upon Leu-382 → Val substitution in human cytochrome P450 1A2.  Drug Metab. Disp. 38:1039-1045.              

Education:

Post-doctoral Training

Postdoctoral fellow, 1991-92, University of California, San Francisco, California

Graduate Training

M.S. in Biology, 1981, Maria Curie-Sklodowska University, Lublin, Poland
Ph.D. in Chemistry, 1991, Clarkson University, Potsdam, New York

 

Positions:

 

Post-doctoral Fellow, 1991-1992, Department of Pediatrics, University of California, San Francisco, CA

Research Associate, 1992-1995, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ

Assistant Research Scientist, 1995-1997, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ

Associate Research Scientist, 1998, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ

Assistant Professor, August 1998-2004, Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV

Associate Professor, July 2004-present, Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV

 

Research Interests:

 

Structure and function of cytochromes P450
Homology modeling of enzyme structure
Utilization of molecular modeling methods to study protein function
P450-mediated drug metabolism and carcinogenesis

 

Research Summary

 

My current research focuses on structure-function relationships of human cytochromes P450 1A1 and 1A2, which play a key role in the metabolic activation of chemical carcinogens and in the metabolism of drugs. The objective of this research is to elucidate the structural basis for the function of these enzymes using a combination of molecular modeling and experimental methods, such as heterologous expression, site-directed mutagenesis and biochemical assays. We apply molecular modeling methods, such as molecular dynamics, to predict product profiles and kinetic constants, as well as NMR techniques, which will help to characterize enzyme-substrate interactions in the active site.

This research lies at the interface between the application of the theory of computational chemistry and the utilization of experimental methods, such as NMR and molecular biology techniques, and has a potential for advancing our understanding of how enzymes activate or deactivate drugs and xenobiotics.

 

Research Techniques:

 

Molecular modeling , homology modeling of proteins
Heterologous expression of mammalian enzymes in E. coli
Protein purification and analysis - chromatography, SDS-PAGE, Western blots, etc.
Enzyme assays, enzyme kinetics - spectroscopic methods, HPLC
Molecular biology - gene cloning and site-directed mutagenesis

 

Recent  Grants:

Structural basis for functional differences between human cytochromes P450 1A1 and 1A2, 1999- 2000 (WVU Senate Research Grant)
Active site model of cytochromes P450 1A1 and 1A2, 2000-2002 (NIH/NCI)
Structural determinants of P450 1A1 and 1A2 specificity. 2001-2006 (NIH/NCRR)
Cytochrome P450-reductase interactions in the P450 1A subfamily, 2006 (Bridge Grant, WVU HSC)
Cytochrome P450-reductase interactions in P450 1A subfamily, 2007-2010 (NIH/NIGMS)
 

Teaching:

Professional:

Phar 731: Biopharmaceutics and Pharmacokinetics

Graduate:

Phar 779: Drugs Discovery and Development
Phar 780: Introduction to Molecular Modeling
Phar 781: Drug Metabolism

 

Special Service:

 

Member of Editorial Board of Drug Metabolism and Disposition
Workshop Presenter for Expanding Your Horizons in Math and Science Conferences organized by AWIS-WV

 

Professional Memberships:

 

American Association of Colleges of Pharmacy
American Chemical Society
American Society for Pharmacology and Therapeutics
Association for Women in Science
International Society for the Study of Xenobiotics

Sara Crile Allen and James Frederick Allen Lung Cancer