Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice.
Ataxia telangiectasia (AT) is a hereditary human disorder resulting in a wide variety of clinical manifestations, including progressive neurodegeneration, immunodeficiency, and high incidence of lymphoid tumors. Cells from patients with AT show genetic instability, hypersensitivity to radiation, and a continuous state of oxidative stress. Oxidative stress and genetic instability, including DNA deletions, are involved in carcinogenesis. We examined the effect of dietary supplementation with the thiol-containing antioxidant N-acetyl-l-cysteine (NAC) on levels of oxidative DNA damage and the frequency of DNA deletions in Atm-deficient (AT-mutated) mice. We confirmed that Atm-deficient mice display an increased frequency of DNA deletions (Bishop et al., Cancer Res 2000;60:395). Furthermore, we found that Atm-deficient mice have significantly increased levels of 8-OH deoxyguanosine, an indication of oxidative DNA damage. Dietary supplementation with NAC significantly reduced 8-OH deoxyguanosine level and the frequency of DNA deletions in Atm-deficient mice. These levels were similar to the levels in wild-type mice. Our findings demonstrate that NAC counteracts genetic instability and suggest that genetic instability may be a consequence of oxidative stress in Atm-deficient mice.
Department of Pathology, Geffen School of Medicine and School of Public Health, University of California-Los Angeles, 650 Charles E. Young Drive South, Los Angeles, CA 90024, USA.
Ramune
R
Reliene
Elvira
E
Fischer
Robert H
RH
Schiestl
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019587:Dietary Supplements; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D042822:Genomic Instability; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D013438:Sulfhydryl Compounds; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D013438:Sulfhydryl Compounds; D025521:Tumor Suppressor Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D003849:Deoxyguanosine; D000111:Acetylcysteine