Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdx(a) encoding glucose 6-phosphate dehydrogenase

• Published in: Free radical biology & medicine 2003-01, Vol.34 (2), p.226-232
• Main Authors: Felix, Klaus, Rockwood, Lynne D, Pretsch, Walter, Bornkamm, Georg Wilhelm, Janz, Siegfried
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Base Sequence; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Lac Operon - genetics; Mice; Mutagenesis; Oxidation-Reduction; Oxidative Stress; Recombination, Genetic - genetics; Sequence Deletion - genetics; Spleen - enzymology; Spleen - metabolism
• ISSN: 0891-5849
• DOI: 10.1016/S0891-5849(02)01243-1

Mice harboring the activity-attenuated Gpdx(a-m2Neu) allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.8-fold increase in mutant frequencies in lacZ. A concomitant 3-fold reduction in catalase activity (dependent upon NADPH) indicated that the in vivo supply of G6PD-generated NADPH was insufficient. An additional 3-fold increase in oxidized glutathione suggested that redox control was disturbed in G6PD-deficient spleens. These findings indicate that G6PD is required for limiting oxidative mutagenesis in the mouse spleen. Gpdx(a-m2Neu) is the first hypomorphic allele of a mouse housekeeping gene associated with elevated somatic mutagenesis in vivo.