Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Novel Strategies to Ameliorate Radiation Injury: A Possible Role for Tetrahydrobiopterin

Author(s): Maaike Berbee, Qiang Fu, K. Sree Kumar and Martin Hauer-Jensen

Affiliation: Department of Radiation Oncology (Maastro), Maastricht University Medical Center, Dr Tanslaan 12, 6229 ET Maastricht, The Netherlands.

Keywords: Radiation injuries, radioprotection, endothelial dysfunction, nitric oxide synthase, tetrahydrobiopterin, HMG-CoA reductase, γ-tocotrienol, injuries, endothelial, nitric oxide, HMG-CoA, radiation, (NOS), BH4, oxidative, radiotherapy, amifostine, (eNOS), (ROS), (SOD), mRNA, (iNOS), NADPH, (NHA), (GTP), (GTPCH), (LPS), Folates, (AT1R), (ARBs), -tocotrienol, Ascorbic Acid, GFRP

Abstract:

Novel pharmacological strategies are urgently needed to prevent or reduce radiation-induced tissue injury. Microvascular injury is a prominent feature of both early and delayed radiation injury. Radiation-induced endothelial dysfunction is believed to play a key role in the pathogenesis of post-irradiation tissue injury. Hence, strategies that could prevent or improve endothelial malfunction are expected to ameliorate the severity of radiation injury. This review focuses on the therapeutic potential of the nitric oxide synthase (NOS) cofactor 5,6,7,8-tetrahydrobiopterin (BH4) as an agent to reduce radiation toxicity. BH4 is an essential cofactor for all NOS enzymes and a critical determinant of NOS function. Inadequate availability of BH4 leads to uncoupling of the NOS enzyme. In an uncoupled state, NOS produces the highly oxidative radicals superoxide and peroxynitrite at the cost of NO. Under conditions of oxidative stress, such as after radiation exposure, BH4 availability might be reduced due to the rapid oxidation of BH4 to 7,8-dihydrobiopterin (7,8-BH2). As a result, free radical – induced BH4 insufficiency may increase the oxidative burden and hamper NOdependent endothelial function. Given the growing evidence that BH4 depletion and subsequent endothelial NOS uncoupling play a major role in the pathogenesis of endothelial dysfunction in various diseases, there is substantial reason to believe that improving post-irradiation BH4 availability, by either supplementation with it or modulation of its metabolism, might be a novel strategy to reduce radiation-induced endothelial dysfunction and subsequent tissue injury.

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Article Details

VOLUME: 11
ISSUE: 11
Page: [1366 - 1374]
Pages: 9
DOI: 10.2174/1389450111009011366