Namandje N. Bumpus

Department Affiliation: Primary:  Pharmacology and Molecular Sciences;
Secondary: Medicine, Division of Clinical Pharmacology
Degree: Ph.D., University of Michigan
Rank: Assistant Professor
Telephone Number : 410-955-0562
Fax Number: 410-955-3023
E-mail address: nbumpus1@jhmi.edu
School of Medicine Address: Biophysics 307-A, 725 N. Wolfe Street, Baltimore, MD  21205 

Drug Metabolism and preclinical drug development; small molecule mass spectrometry; targeted metabolomics; antiviral drug-induced toxicity; modulation of cellular signaling pathways by reactive metabolites.

Our laboratory uses mass spectrometry and molecular pharmacology based approaches to investigate the biotransformation of clinically used drugs by the cytochromes P450s. The cytochromes P450 are crucial to drug disposition as they are responsible for the metabolism of an estimated 75% of currently marketed drugs. Cytochrome P450-mediated biotransformation of drugs most often results in the production of hydrophilic metabolites that can be readily excreted from the body; however, in certain instances toxic metabolites are formed that can stimulate cell death and organ failure. Research in our laboratory focuses on defining a role for cytochrome P450-dependent metabolites in the drug-induced acute liver failure that is associated with certain antiviral drugs used to treat HIV and hepatitis C. To approach this, we develop novel mass spectrometry assays to measure and discover drug metabolites. In addition, we isolate these metabolites and probe their pharmacology and toxicology using both in vitro and in vivo models. In doing so, we examine modulation of cellular signaling pathways by these metabolites using molecular techniques and mass spectrometry-based metabolomics to spur discovery of biomarkers and novel therapeutic targets for drug-induced liver failure. Further, once we have elucidated the chemical structure of a toxic metabolite we test whether blocking the site of metabolism can inhibit the toxicity without altering the pharmacologic activity of the drug. The long-term goal of our laboratory is gain information that can be used to develop next generation therapies that are devoid of these toxic events by preventing the formation of a toxic metabolite and/or by developing strategies for preventing toxicity using concomitant therapy.   

Representative Publications:  

• Yanakakis, L.J. and Bumpus, N.N. 2012. Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metabolism and Disposition 40(4):803-814.  Pub Med Reference
  
  
• Bumpus, N.N. and Johnson, E.F. 2011. 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor α-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein kinase-independent. Journal of Pharmacology and Experimental Therapeutics 339(3):886-895. Pub Med Reference
  
  
• Bumpus, N.N. 2011. Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicology and Applied Pharmacology 257(2):227-234. Pub Med Reference
   
• Bumpus, N.N. and Hollenberg P.F.  Cross-linking of cytochrome P450 2B6 to NADPH-cytochrome P450 reductase: identification of a potential site of interaction. Journal of Inorganic Biochemistry 104(4):485-488, 2010.  Pub Med Reference

• Bumpus, N.N. and Hollenberg P.F. 2008. Investigation of the mechanisms underlying the effects of the K262R mutation of P450 2B6 on catalytic activity.  Molecular Pharmacology 74(4):990-999, 2008.  Pub Med Reference 

• Hollenberg P.F., Kent U.M. and Bumpus N.N.  Mechanism-based inactivation  of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications. Chemical Research in Toxicology 21(1):189-205, 2008.  Pub Med Reference   

• Bumpus, N.N., Kent U.M. and Hollenberg P.F.  Metabolism of efavirenz and 8-hydroxyefavirenz by P450 2B6 leads to inactivation by two distinct mechanisms.  Journal of Pharmacology and Experimental Therapeutics 318(1):345-351, 2006.  Pub Med Reference    

• Bumpus, N.N., Sridar, C., Kent U.M. and Hollenberg P.F.  The Naturally occurring K262R mutant of P450 2B6 exhibits alterations in substrate metabolism and inactivation. Drug Metabolism and Disposition 33(6):795-802, 2005.  Pub Med Reference   

Other graduate programs in which Dr. Bumpus participates: None