title: Hypersensitivity of ataxia-telangiectasia fibroblasts to a nitric oxide donor.
abstract: Ataxia-telangiectasia (A-T) is a human autosomal recessive disease characterised by immunodeficiency, extreme sensitivity to ionising radiation and progressive cerebellar ataxia. The defective gene has recently been cloned and is a member of the phosphatidylinositol 3-kinase family. We have investigated the possibility that the neurodegeneration in A-T might be induced by an endogenously formed mutagen causing radiation-like damage. Nitric oxide is known to be formed in the cerebellum and we present evidence that A-T fibroblasts are hypersensitive to killing by the nitric oxide donor S-nitrosoglutathione (GSNO), as are fibroblasts from a radiosensitive individual without ataxia. Killing was determined as loss of colony forming ability. GSNO induces dose-dependent DNA strand breakage, but to no greater extent in A-T fibroblasts. Breakdown of GSNO to nitrite and nitrate appears to occur to the same extent in both normal and A-T fibroblasts. Cell killing by GSNO appears to be associated in both types of cell with formation of nitrite, rather than nitrate, as the ultimate oxidation product of nitric oxide.
authors.affiliation: MRC Cell Mutation Unit, School of Biological Sciences, University of Sussex, Falmer, Brighton, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Green
authors.forename: A J
authors.initials: AJ
authors.lastname: Marcovitch
authors.forename: S A
authors.initials: SA
authors.lastname: Harcourt
authors.forename: J E
authors.initials: JE
authors.lastname: Lowe
authors.forename: I C
authors.initials: IC
authors.lastname: Green
authors.forename: C F
authors.initials: CF
authors.lastname: Arlett
mesh_terms: D001260:Ataxia Telangiectasia / Q000139:chemically induced* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004342:Drug Hypersensitivity / Q000209:etiology*; D005347:Fibroblasts / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis*; D009603:Nitroso Compounds / Q000633:toxicity*; D012016:Reference Values; D026422:S-Nitrosoglutathione
chemical_list: D009603:Nitroso Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione