Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound.
Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1, 2-diolate (DEA/NO) at an initial concentration of 0.6 mM while generating superoxide ion at the rate of 1 microM/min with the hypoxanthine/xanthine oxidase (HX/XO) system induced C:G-->T:A transition mutations in codon 248 of the p53 gene. This pattern of mutagenicity was not seen by 'fish-restriction fragment length polymorphism/polymerase chain reaction' (fish-RFLP/PCR) on exposure to DEA/NO alone, however, exposure to HX/XO led to various mutations, suggesting that co-generation of NO and superoxide was responsible for inducing the observed point mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as well as DNA single- and double-strand breaks under these conditions, while 0.6 mM DEA/NO in the absence of HX/XO had no significant effect on these parameters. The results show that a point mutation seen at high frequency in certain common human tumors can be induced by simultaneous exposure to reactive oxygen species and a NO source.
Souici
A C
AC
Institute of Pharmacology and Toxicology, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Mirkovitch
J
J
Hausel
P
P
Keefer
L K
LK
Felley-Bosco
E
E
D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D001980:Bronchi / Q000166:cytology; D002461:Cell Line, Transformed; D003062:Codon / Q000737:chemistry / Q000235:genetics*; D004249:DNA Damage; D053938:DNA Fragmentation; D004357:Drug Synergism; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology; D016158:Genes, p53 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology / Q000633:toxicity*; D019271:Hypoxanthine / Q000378:metabolism; D015227:Lipid Peroxidation; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000633:toxicity*; D009589:Nitrogen Oxides; D017354:Point Mutation; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D003062:Codon; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D013481:Superoxides; D019271:Hypoxanthine; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D014969:Xanthine Oxidase