Novel strategies to ameliorate radiation injury: a possible role for tetrahydrobiopterin

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 NO-dependent 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.

Fig. (1)

Model of radiation-induced endothelial dysfunction. Radiation-induced oxidative stress may decrease the availability of the eNOS cofactor BH4 due to rapid oxidation of BH4 to 7,8-BH2. Diminished BH4 availability may induce eNOS uncoupling and thereby limit NO production and increase O₂⁻ production. Endothelial NOS–dependent O₂⁻ may reduce BH4 levels even further.

Fig. (2)

Schematic representation of NOS function under coupled and uncoupled conditions. Under coupled conditions, NOS enzymes mainly produce l-citrulline and NO. Suboptimal concentrations of BH4 may cause NOS uncoupling. Under such conditions, O₂⁻ is produced at the cost of NO.

Fig. (3)

BH4 synthesis. BH4 is synthesized from GTP by a de novo pathway. The conversion of GTP to 7,8-dihydroneopterin triphosphate by GTPCH is the rate-limiting step of this pathway. The salvage pathway generates BH4 from its oxidized forms. The salvage pathway is also necessary to convert exogenous sepiapterin into BH4. GTPCH: GTP cyclohydrolase I; PTPS: 6-pyruvoyl-tetrahydropterin synthase; SR: sepiapterin reductase; DHFR: dihydrofolate reductase.