• Rupak Pathak, Snehalata A Pawar, Qiang Fu, Prem K Gupta, Maaike Berbée, Sarita Garg, Vijayalakshmi Sridharan, Wenze Wang, Prabath G Biju, Kimberly J Krager, Marjan Boerma, Sanchita P Ghosh, Amrita K Cheema, Howard P Hendrickson, Nukhet Aykin-Burns, and Martin Hauer-Jensen.
• 1 Division of Radiation Health, University of Arkansas for Medical Sciences , Little Rock, Arkansas.
• Antioxid. Redox Signal. 2014 Mar 20; 20 (9): 1436-46.

AimsThe free radical scavenger and nitric oxide synthase cofactor, 5,6,7,8-tetrahydrobiopterin (BH4), plays a well-documented role in many disorders associated with oxidative stress, including normal tissue radiation responses. Radiation exposure is associated with decreased BH4 levels, while BH4 supplementation attenuates aspects of radiation toxicity. The endogenous synthesis of BH4 is catalyzed by the enzyme guanosine triphosphate cyclohydrolase I (GTPCH1), which is regulated by the inhibitory GTP cyclohydrolase I feedback regulatory protein (GFRP). We here report and characterize a novel, Cre-Lox-driven, transgenic mouse model that overexpresses Gfrp.ResultsCompared to control littermates, transgenic mice exhibited high transgene copy numbers, increased Gfrp mRNA and GFRP expression, enhanced GFRP-GTPCH1 interaction, reduced BH4 levels, and low glutathione (GSH) levels and differential mitochondrial bioenergetic profiles. After exposure to total body irradiation, transgenic mice showed decreased BH4/7,8-dihydrobiopterin ratios, increased vascular oxidative stress, and reduced white blood cell counts compared with controls.Innovation And ConclusionThis novel Gfrp knock-in transgenic mouse model allows elucidation of the role of GFRP in the regulation of BH4 biosynthesis. This model is a valuable tool to study the involvement of BH4 in whole body and tissue-specific radiation responses and other conditions associated with oxidative stress.

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