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Administration of a novel β‐hydroxybutyrate ester after radiation exposure suppresses in vitro lethality and chromosome damage, attenuates bone marrow suppression in vivo
Author(s) -
Kemper Martin F,
Miller Alexandra,
Pawlosky Robert J,
Veech Richard
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.627.3
Subject(s) - bone marrow , ex vivo , dna damage , in vivo , chemistry , pharmacology , cancer research , biochemistry , biology , in vitro , immunology , genetics , dna
Cellular mechanisms to protect against and repair radiation damage depend on reducing equivalents from oxidative metabolism. Two recent studies explored compounds (ex. Ex‐Rad and TP‐508) with efficacy in preventing injury or reducing its severity but neither takes advantage of cellular metabolism to this end. We report for the first time that a novel ketone body ester (KE) protects against injury and death in cells and animals exposed to several types of radiation. The unique metabolism of ketone bodies shifts biochemical set points, particularly of the NADP/H system which is essential to cellular antioxidant function and oxidative damage repair. Additionally, the demonstrated activity of the ketone bodies as histone deacetylase inhibitors and enhancers of DNA repair may make these compounds uniquely suited to combat radiation injury. We show that addition of KE to culture media provides significant protection to cultured osteoblasts against γ‐radiation lethality when administered before or after radiation. KE significantly attenuated gamma radiation induced chromosomal injury in an escalating dose model (60–70% reduction). Ketone ester supplementation also significantly reduced proton radiation induced γH2Ax foci, a marker of double stranded DNA breaks, and overall proton radiation lethality. KE protection extends to other radiation types, with an average dose reducing factor of 30%. In vivo confirmation of these findings is ongoing, but preliminary data indicates that many bone marrow chromosomal damage markers were attenuated by 50% when KE was administered by gavage 24 hours after γ‐radiation exposure. Importantly, the reticulocyte/erythrocyte ratio in bone marrow, a marker of erythrogenesis and an important indicator for survival at the radiation exposure level studied was significantly rescued by KE. Support or Funding Information Funding was provided by the NIH/NIAAA, Department of Defense and Defense Medical Research and Development Program