Efavirenz (EFV) and nevirapine (NVP) are currently prescribed antiretroviral drugs of the same class that are hepatotoxic. Recently, a major role for cellular signaling pathways in modulating toxicity downstream of EFV metabolism has been reported in vitro using primary human hepatocytes. Increased oxidative stress and the upregulation of the proapoptotic protein BimEL (Bcl-2 interacting mediator of cell death extra long) have been demonstrated to be crucial in the stimulation of EFV-induced cell death, and NVP appears to modulate hepatocyte death via the same mechanism. The goal of this proposal is to determine the manner in which EFV and NVP upregulate BimEL, while also gaining a mechanistic understanding of the events downstream of BimEL that mediate the hepatocyte death.
The aims are as follows: (1) Test whether genetic deficiency of proapoptotic BimEL results in protection against EFV- and NVP-mediated cell death in vivo: BimEL null mice will be used to determine whether the absence of BimEL renders mice resistant to hepatotoxicity stimulated by these compounds; RNA interference studies in hepatocytes will be used to determine the role of effector proteins, Bax and Bak, that are downstream of BimEL in modulating EFV- and NVP-induced hepatocyte death; siRNA and reporter gene assays will be used to define the mechanism by which EFV and NVP regulate the transcription of BimEL; (2) determine if proapoptotic pathways that are activated by antiretrovirals in primary human hepatocytes are also activated in macaques receiving antiretroviral therapy; (3) probe a role for alteration of the glutathione pathway in EFV- and NVP-induced hepatotoxicity; the effects of these compounds on the glutathione pathway will be examined using a mass spectrometry-based approach that will precisely quantitate the intermediates/products of this pathway; RNA interference will be used to define the role of enzymes in the glutathione pathway in EFV- and NVP-induced hepatotoxicity. It is expected that completion of the proposed studies will lead to the identification of novel therapeutic targets for the potential prevention and treatment of EFV- and NVP-mediated hepatotoxicity.
Drug-induced hepatotoxicity is a major cause of acute liver failure. The goal of this project is to investigate the mechanism(s) underlying the liver toxicity associated with the use of certain antiretroviral drugs to spur discovery of therapeutic strategies for the prevention and treatment of this adverse event.
|Cox, Philip M; Bumpus, NamandjÃ© N (2016) Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6. ChemMedChem 11:2630-2637|
|Lade, Julie M; To, Elaine E; Hendrix, Craig W et al. (2015) Discovery of Genetic Variants of the Kinases That Activate Tenofovir in a Compartment-specific Manner. EBioMedicine 2:1145-52|
|Seamon, Kyle J; Hansen, Erik C; Kadina, Anastasia P et al. (2014) Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization. J Am Chem Soc 136:9822-5|
|Avery, Lindsay B; Bumpus, NamandjÃ© N (2014) Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. Mol Pharmacol 85:1-10|
|Hersman, Elisabeth M; Bumpus, NamandjÃ© N (2014) A targeted proteomics approach for profiling murine cytochrome P450 expression. J Pharmacol Exp Ther 349:221-8|
|Cox, Philip M; Bumpus, NamandjÃ© N (2014) Structure-Activity Studies Reveal the Oxazinone Ring Is a Determinant of Cytochrome P450 2B6 Activity Toward Efavirenz. ACS Med Chem Lett 5:1156-1161|
|Lade, Julie M; Avery, Lindsay B; Bumpus, NamandjÃ© N (2013) Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob Agents Chemother 57:5067-79|
|To, Elaine E; Hendrix, Craig W; Bumpus, Namandje N (2013) Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues. Biochem Pharmacol 86:979-90|
|Avery, Lindsay B; VanAusdall, Jennifer L; Hendrix, Craig W et al. (2013) Compartmentalization and antiviral effect of efavirenz metabolites in blood plasma, seminal plasma, and cerebrospinal fluid. Drug Metab Dispos 41:422-9|