Moderate G6PD deficiency increases mutation rates in the brain of mice

Klaus Felix; Lynne D Rockwood; Walter Pretsch; Jagadeesan Nair; Helmut Bartsch; Georg-Wilhelm Bornkamm; Siegfried Janz

doi:10.1016/S0891-5849(02)00756-6

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Moderate G6PD deficiency increases mutation rates in the brain of mice

Journal article

Peer reviewed

Moderate G6PD deficiency increases mutation rates in the brain of mice

Klaus Felix, Lynne D Rockwood, Walter Pretsch, Jagadeesan Nair, Helmut Bartsch, Georg-Wilhelm Bornkamm and Siegfried Janz

Free radical biology & medicine, Vol.32(7), pp.663-673

2002

DOI: 10.1016/S0891-5849(02)00756-6

PMID: 11909700

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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 (∼3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts (∼13-fold increase in ethenodeoxyadenosine and ∼5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates (∼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.

Endogenous oxidative stress

In vivo mutagenicity reporter gene

Free radicals

Glucose-6-phoshpate dehydrogenase

lacZ

Etheno DNA adducts

Details

Title: Subtitle: Moderate G6PD deficiency increases mutation rates in the brain of mice
Creators: Klaus Felix - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Lynne D Rockwood - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Walter Pretsch - Institute of Mammalian Genetics, Neuherberg, Germany
Jagadeesan Nair - Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
Helmut Bartsch - Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
Georg-Wilhelm Bornkamm - Institute of Molecular Biology and Tumor Genetics, Munich, Germany
Siegfried Janz - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.32(7), pp.663-673
DOI: 10.1016/S0891-5849(02)00756-6
PMID: 11909700
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Language: English
Date published: 2002
Academic Unit: Pathology
Record Identifier: 9984083218802771

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