Title: The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations.
Authors: O'Connor, Roddy S; Guo, Lili; Ghassemi, Saba; Snyder, Nathaniel W; Worth, Andrew J; Weng, Liwei; Kam, Yoonseok; Philipson, Benjamin; Trefely, Sophie; Nunez-Cruz, Selene; Blair, Ian A; June, Carl H; Milone, Michael C
Published In Sci Rep, (2018 04 19)
Abstract: Etomoxir (ETO) is a widely used small-molecule inhibitor of fatty acid oxidation (FAO) through its irreversible inhibitory effects on the carnitine palmitoyl-transferase 1a (CPT1a). We used this compound to evaluate the role of fatty acid oxidation in rapidly proliferating T cells following costimulation through the CD28 receptor. We show that ETO has a moderate effect on T cell proliferation with no observable effect on memory differentiation, but a marked effect on oxidative metabolism. We show that this oxidative metabolism is primarily dependent upon glutamine rather than FAO. Using an shRNA approach to reduce CPT1a in T cells, we further demonstrate that the inhibition of oxidative metabolism in T cells by ETO is independent of its effects on FAO at concentrations exceeding 5 μM. Concentrations of ETO above 5 μM induce acute production of ROS with associated evidence of severe oxidative stress in proliferating T cells. In aggregate, these data indicate that ETO lacks specificity for CTP1a above 5 μM, and caution should be used when employing this compound for studies in cells due to its non-specific effects on oxidative metabolism and cellular redox.
PubMed ID: 29674640
MeSH Terms: Carnitine O-Palmitoyltransferase/antagonists & inhibitors*; Carnitine O-Palmitoyltransferase/metabolism; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors/pharmacology*; Epoxy Compounds/pharmacology*; Humans; Oxidative Stress/drug effects*; T-Lymphocytes/cytology; T-Lymphocytes/drug effects; T-Lymphocytes/metabolism