Dr. Bumpus’ 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 responsible for the metabolism of an estimated 75 percent 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.
The Bumpus lab focuses on defining a role for cytochrome P450-dependent metabolites in drug-induced acute liver failure associated with certain antiviral drugs used to treat HIV and hepatitis C. To approach this, they develop novel mass spectrometry assays to measure and discover drug metabolites. In addition, they isolate these metabolites and probe their pharmacology and toxicology using both in vitro and in vivo models. In doing so, they 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 the chemical structure of a toxic metabolite has been elucidated, they test whether blocking the site of metabolism can inhibit the toxicity without altering the pharmacologic activity of the drug. The long-term goal of the lab is to 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.
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Lade JM, Avery LB, Bumpus NN. “Human Biotransformation of the Non-nucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross Species Metabolism Comparison.” Antimicrob Agents Chemother. 2013 Aug 5.
Hendrix C, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, Salata R, Soto-Torres L, Patterson K, Minnis AA, Gandham S, Gomez K, Richardson BA and Bumpus NN. 2013. “MTN-001: Randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments.” PLoS One 8(1):e55013.
Avery LB, Vanausdall JL, Hendrix CW and Bumpus NN. 2013. “Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma and Cerebrospinal Fluid.” Drug Metabolism and Disposition. 41(2):422-9.
Anton PA, Cranston RD, Kashuba A, Hendrix C, Bumpus NN, Richardson-Harman N, Elliott J, Janocko L, Khanukhova E, Dennis RA, Cumberland WG, Ju C, Carballo-Diéguez A, Mauck C, McGowan IM. 2012. “RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic and Pharmacodynamic Study of Tenofovir 1% Gel Compared to Oral Tenofovir Disoproxil Fumerate.” AIDS Research and Human Retroviruses 28(11):1412-21.
Lu Y, Hendrix CW and Bumpus NN. 2012. “Cytochrome P450 3A5 Plays a Prominent Role in the Oxidative Metabolism of the Anti-HIV Drug Maraviroc.” Drug Metabolism and Disposition 40(12):2221-30.
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C; the Partners PrEP Study Team. 2012. “Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women.” New England Journal of Medicine 367(5):399-410.
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.
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 Pharmacolog. 257(2):227-234.