Tuttle, S., Stamato, T., Perez, M. L. and Biaglow, J. Glucose-6-phosphate Dehydrogenase and the Oxidative Pentose Phosphate Cycle Protect Cells against Apoptosis Induced by Low Doses of Ionizing Radiation.

The initial and rate-limiting enzyme of the oxidative pentose phosphate shunt, glucose-6-phosphate dehydrogenase (G6PD), is inhibited by NADPH and stimulated by NADP . Hence, under normal growth conditions, where NADPH levels exceed NADP levels by as much as 100-fold, the activity of the pentose phosphate cycle is extremely low. However, during oxidant stress, pentose phosphate cycle activity can increase by as much as 200-fold over basal levels, to maintain the cytosolic reducing environment. G6PD-deficient (G6PD⁻) cell lines are sensitive to toxicity induced by chemical oxidants and ionizing radiation. Compared to wild-type CHO cells, enhanced sensitivity to ionizing radiation was observed for G6PD⁻ cells exposed to single-dose or fractionated radiation. Fitting the single-dose radiation response data to the linear-quadratic model of radiation-induced cytotoxicity, we found that the G6PD⁻ cells exhibited a significant enhancement in the α component of radiation-induced cell killing, while the values obtained for the β component were similar in both the G6PD⁻ and wild-type CHO cell lines. Here we report that the enhanced α component of radiation-induced cell killing is associated with a significant increase in the incidence of ionizing radiation-induced apoptosis in the G6PD⁻ cells. These data suggest that G6PD and the oxidative pentose phosphate shunt protect cells from ionizing radiation-induced cell killing by limiting the incidence of radiation-induced apoptosis. The sensitivity to radiation-induced apoptosis was lost when the cDNA for wild-type G6PD was transfected into the G6PD⁻ cell lines. Depleting GSH with l-BSO enhanced apoptosis of K1 cells while having no effect in the G6PD⁻ cell line