C. Varricchio, K. Beirne, C. Heard, B. Newland, M. Rozanowska, A. Brancale, M. Votruba, Free Radical Biology and Medicine, 2019, doi:10.1016/j.freeradbiomed.2019.11.030.
Beneficial effects of idebenone are dependent on the expression of NQO1 in cells. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials.
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