Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase.
Nitric oxide (NO) has been shown to be involved in a number of physiological processes. In the presence of oxygen, this reactive diatomic molecule is capable of generating reactive nitrogen oxide species (NOx) which possess both nitrosating and oxidizing ability for various substrates, including certain biological macromolecules. This report shows the inhibition of the DNA repair protein, O6-methylguanine-DNA-methyltransferase, by Et2N[N(O)NO]Na (DEA/NO), a compound which decomposes with concurrent release of NO. The inhibition of the purified transferase activity by NO was dose- and time-dependent and the extent of inhibition by DEA/NO corresponded to the total quantity of NO released. This inhibitory effect by NO was also demonstrated to be reversible over time. The reaction of the NO released from DEA/NO with cysteine under aerobic conditions resulted in the formation of an S-nitrosothiol adduct, suggesting that a similar adduct could be responsible for the inactivation.
Laval
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Groupe Radiochimie de l'ADN, U 247 INSERM, Institut Gustave-Roussy, Villejuif, France.
Wink
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DA
D000818:Animals; D002330:Carmustine / Q000633:toxicity; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D008623:Mercaptoethanol; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D026403:S-Nitrosothiols; D014407:Tumor Cells, Cultured
D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005978:Glutathione; D003545:Cysteine; D002330:Carmustine