Dr. Totah

Dr. Totah

Rheem Totah, MS, PhD

Office: H-172M
Box: 357610
Email: rtotah@uw.edu


Adjunct Associate Professor, Oral Health Sciences
Assistant Professor of Medicinal Chemistry

Interests

Research in the Totah lab is broadly centered on drug-endogenous substrate interactions. Cytochrome P450 enzymes are mainly known for their ability to metabolize xenobiotics. However, some isozymes are also involved in the metabolism of endogenous substrates such as retinoic acid, steroids and essential fatty acids. We are interested in studying the xenobiotics-endogenous substrate interaction and its potential for inducing tissue-specific toxicity in the kidney, heart, and lung. We are also involved in translational research and collaborate with colleagues in the medical center to bridge together wet-lab science and clinical science. On a daily basis we use molecular biology tools, LC-MS/MS analysis, kinetic analysis and chemical synthesis to understand the biochemical and functional aspects of various P450 enzymes.

A separate area of research focuses on cytochrome P450 BM3, and several mutants, as a model system to study the mechanism of electron transfer from NADPH to the heme and the catalytic mechanism of mammalian P450 enzymes.

Publications

  1. Kaspera R, Naraharisetti SB, Tamraz B, Sahele T, Kwok P-Y, Marciante K, Heckbert SR, Psaty BM, Totah RA. “In Vitro Metabolism of Cerivastatin by CPY2C8 Variants Found in Patients Experiencing Rhabdomyolysis.” Pharmacogenetics and Genomics. In press.
  2. Naraharisetti SB, Lin YS, Rieder M, Marciante K, Psaty BM, Thummel KE, Totah RA. “Human Liver Expression of CYP2C8: gender, age and genotype effects.” Drug Metab. Dispos. 38(6):889-93 (2010).
  3. Lee C, Neul D, Clouser-Roche A, Dalvie D, Jiang J, Jones III JP, Wester M, Zientek M, Totah RA. “Identification of Novel Substrates for CYP2J2.” Drug Metab. Disp. 38:347-356 (manuscript featured on the cover of February 2010 edition).
  4. Smith, H., Jones, JP III, Kalhorn, T., Farin, F., Stapleton, P., Davis, C., Perkins, J., Blough, D., Hebert M., Thummel, K., Totah, R.A. “Role of Cytochrome P450 2C8 and 2J2 genotype in calcineurin inhibitor induced chronic kidney disease.” Pharmacogenetics and Genomics. Nov;18(11):943-53 (2008).
  5. Marciante, K., Totah, R.A., Heckbert, S., Smith, N., LeMaitre, R., Lumley, T., Rice, K., Hindorff, L., Bis, J., Hartman, B., Psaty, B, “Common Variation in Cytochrome P450 Epoxygenase Genes and the Risk of Incident Non-Fatal Myocardial Infarction and Ischemic Stroke.” Pharmacogenet Genomics Jun;18(6):535-543 (2008).
  6. Totah, R.A., Sheffels, P., Roberts, T., Whittington, D., Thummel, K., Kharasch, ED. “Role of CYP2B6 in Stereoselective Human Methadone Metabolism.” Anesthesiology 108:363-74 (2008).
  7. Totah, R.A., Allen, KE, Sheffels, P., Whittington, D., and Kharasch, E.D. “Enantiomeric metabolic interactions and stereoselective human methadone metabolism.” J Pharmacol Exp Ther. 321:389-399 (2007).
  8. Gaedigk, A., Baker, D.W., Totah, R.A., Gaedigk, R., Pearce, R.E., Vyhlidal, C.A., Zeldin, D.C., and Leeder, J.S. “Variability of CYP2J2 expression in human fetal tissues.” J Pharmacol Exp Ther. 319:523-532 (2006).
  9. Totah, R.A., Rettie, A.E. “Principles of drug metabolism, enzymes and tissues.” Comprehensive Drug Metabolism, 2nd ed. Vol. 5 (2006).
  10. Totah, R.A., Rettie, A.E. “CYP2C8: Substrates, Inhibitors, Pharmacogenetics and Clinical Relevance.” Clin Pharm Therap. 77: 341-352 (2005).
  11. Hanzlik, R. P., Harriman, S. P., Shaffer, C. L., Koen, Y. M., Totah, R. A., and Cerny, M. A. “The Oxidative Metabolism of Cyclopropylamines: Fate of the Three Carbons and Other Interesting Observations.” Synthesis and Application of Isotopically Labelled Compounds, 8:111-114 (2004).
  12. Huang, W., Lin, Y., McConn II, D., Calamia, J., Totah, R., Isoherranen, N., Glodowski, M., and Thummel, K. “Evidence of Significant Contribution From CYP3A5 to Hepatic Drug Metabolism.” Drug Met Dispos. 12:1434-1445 (2004).
  13. Totah, R. A. and Hanzlik, R. P. “Oxidative and Non-Oxidative Decarboxylation of N-Alkyl-N-phenylglycines by Horseradish Peroxidase: Mechanistic Switching by Hydrogen Peroxide, Oxygen and Solvent Deuterium.” Biochemistry 43:7907-7914 (2004) .
  14. Totah, R. A., and Hanzlik, R. P. “Non-Oxidative Decarboxylation of Glycine Derivatives by a Peroxidase.” J Am Chem Soc. 124:10000-10001 (2002).
  15. Totah, R. A., and Hanzlik, R. P. “Detection of Aminium Ion Intermediates: N-Cyclopropyl versus N-Carboxymethyl Groups as Reporters.” J Am Chem Soc. 123:10107-10108 (2001).

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