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Moderate G6PD deficiency increases mutation rates in the brain of mice. Free Radic Biol Med 2002 Apr 01;32(7):663-73

Date

03/23/2002

Pubmed ID

11909700

DOI

10.1016/s0891-5849(02)00756-6

Abstract

Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain.

Author List

Felix K, Rockwood LD, Pretsch W, Nair J, Bartsch H, Bornkamm GW, Janz S

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anemia, Hemolytic
Animals
Brain
DNA Adducts
DNA Mutational Analysis
Glucosephosphate Dehydrogenase
Glucosephosphate Dehydrogenase Deficiency
Glutathione
Lac Operon
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Mutation
Oxidative Stress
Point Mutation
Polymerase Chain Reaction
Promoter Regions, Genetic
Recombination, Genetic
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2