Dr. Namandjé N. Bumpus Receives Presidential Early Career Award for Scientists and Engineers
Namandjé N. Bumpus was a recipient of both a PhRMA Foundation predoctoral fellowship in pharmacology/toxicology and a pharmacology/toxicology Research Stater Grant. She received a PhD in pharmacology from the University of Michigan and performed thesis research in the laboratory of Dr. Paul F. Hollenberg. Namandjé’s PhRMA Foundation graduate fellowship in pharmacology/toxicology focused on investigation of the effects of a naturally occurring cytochrome P450 (CYP) 2B6 mutation on the ability of the enzyme to become inactivated by known inactivators of the wild-type enzyme. She earned a doctorate in pharmacology in 2007.
As a postdoctoral fellow with Dr. Eric F. Johnson at The Scripps Research Institute, Namandjé studied the regulation of CYP4A and CYP4F genes in mice. Namandjé began her independent research career in 2010 as an assistant professor of Medicine and Pharmacology & Molecular Sciences at The Johns Hopkins University School of Medicine where her initial work investigating the mechanisms of anti-HIV drug-induced toxicities was supported by a PhRMA Foundation Research Starter Grant. She is currently an associate professor at The Johns Hopkins University School of Medicine and the associate dean for institutional and student equity. Her research program is focused on defining the contribution of drug metabolism to the pharmacology and toxicology of drugs used to treat and prevent HIV infection. Namandjé is a recipient of the 2014 Tanabe Young Investigator Award from the American College of Clinical Pharmacology and the 2015 Drug Metabolism Early Career Achievement Award from the American Society for Pharmacology and Experimental Therapeutics. She currently serves on the Drug Metabolism and Disposition editorial board and is a regular member of the NIH Xenobiotic and Nutrient Disposition and Action study section. In 2016 Namandjé was awarded a Presidential Early Career Award for Scientists and Engineers by the Obama administration.
The Research Starter Grant enabled the Bumpus Laboratory to begin to pursue the long-term goal of gaining an understanding the unique pharmacology/toxicology of cytochrome P450 (P450)-dependent metabolites of antiretroviral drugs and the role of drug metabolites in modulating tissue-specific pharmacokinetic-pharmacodynamic relationships of these drugs. In working towards this goal the Bumpus Lab has established a substantial body of work describing the biotransformation of anti-HIV drugs. In particular, they have published several studies focused on the P450-catalyzed metabolism of non-nucleoside reverse transcriptase inhibitors used to treat HIV. This drug class is a cornerstone of HIV therapy and we were the first to report the pathways of both phase 1 and phase 2 metabolism of 2 (rilpivirine and etravirine) of the 4 currently FDA approved and marketed drugs in this class while also demonstrating that these drugs autoinduce their own metabolism via activation of the pregnane X receptor. In addition, the Bumpus Lab put forth a more detailed and expanded P450-dependent metabolism scheme for the most widely prescribed HIV non-nucleoside reverse transcriptase inhibitor, efavirenz. Further, they were the first to characterize the metabolism of dapivirine, a non-nucleoside reverse transcriptase inhibitor in development for topical use in HIV pre-exposure prophylaxis. Through our work with dapvirine the lab established that the several of the major drug metabolizing P450s are present and active in human colorectal and vaginal tissues and that the metabolites formed in these tissues differ from those formed by liver. This study was the first to suggest that the disposition of a drug being used for HIV prevention may vary depending on whether it is administered orally or topically to mucosal tissues that are sites of sexually transmitted HIV infection. All of these studies were funded early on by the Research Starter Grant.
Beyond the non-nucleotide reverse transcriptase inhibitors the Bumpus Lab has also reported a detailed scheme for metabolism of the HIV entry inhibitor maraviroc. These studies revealed that CYP3A5 has a higher capacity to metabolize maraviroc to a major monooxygenated metabolite than CYP3A4. The group leveraged this observation and systematically mutated CYP3A5 toward CYP3A4 using formation of this metabolite as an activity probe to identify residues in CYP3A5 that confer specificity with regard to maraviroc metabolism. The lab found a single residue in CYP3A5 (L57) that when mutated to the corresponding amino acid of CYP3A4 (F57) markedly decreased the ability of CYP3A5 to form this metabolite. Interestingly, when the corresponding residue in CYP3A4 was mutated to towards CYP3A5, CYP3A4 was now able to form the metabolite at levels comparable to CYP3A5. This was the first report of a residue in either CYP3A4 or CYP3A5 that could confer specificity in substrate metabolism. A subsequent clinically study has demonstrated that CYP3A5 polymorphisms may impact maraviroc clearance in patients.
Recent publications:
- Lade JM, Avery LB, Bumpus NN. Human Biotransformation of the Non-nucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross Species Metabolism Comparison. Antimicrobial Agents and Chemotherapy. 2013; 57(10):5067-79.
- To EE, Hendrix CW, Bumpus NN. Dissimilarities in the Metabolism of Antiretroviral Drugs used in HIV Pre-exposure Prophylaxis in Colon and Vagina Tissues. Biochemical Pharmacology. 2013; 86(7):979-90.
- Avery LB and Bumpus NN. Valproic Acid is a Novel Activator of AMP-Activated Protein Kinase and Decreases Liver Mass, Hepatic Fat Accumulation, and Serum Glucose in Obese Mice. Molecular Pharmacology. 2014; 85(1):1-10.
- Hersman EM and Bumpus NN. A Targeted Proteomics Approach for Profiling Murine Cytochrome P450 Expression. Journal of Pharmacology and Experimental Therapeutics. 2014; 349(2):221-8.
- Lu Y, Fuchs EJ, Hendrix CW and Bumpus NN. Cytochrome P450 3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers. Drug Metabolism and Disposition. 2014; 42(11):1796-802.
- Cox P and Bumpus NN. Structure-activity studies reveal the oxazinone ring is a determinant of cytochrome P450 2B6 activity towards efavirenz. ACS Medicinal Chemistry Letters. 2014; 5(10):1156-1161.
- Lade JM, To EE, Hendrix CW and Bumpus NN. Discovery of Genetic Variants of the Kinases that Activate Tenofovir in a Compartment-Specific Manner. EBioMedicine. 2015; 2(9):1145–1152.
EXTERNAL FUNDING SECURED AS A RESULT OF PHRMA SUPPORT NIH R01
GM103853 “Cellular Signaling in Drug-Induced Toxicity” – 2013-2019
