Detection of Concomitant Formation of O6-Carboxymethyl- and O6-Methyl-2'-deoxyguanosine in DNA Exposed to Nitrosated Glycine Derivatives Using a Combined Immunoaffi

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• 作者：Kathryn L. Harrison ; Rebekah Jukes ; Donald P. Cooper ; and David E. G. Shuker
• 刊名：Chemical Research in Toxicology
• 出版年：1999
• 出版时间：January 1999
• 年：1999
• 卷：12
• 期：1
• 页码：106 - 111
• 全文大小：88K
• 年卷期：v.12,no.1(January 1999)
• ISSN：1520-5010

文摘

A previous observation that an N-nitroso-N-carboxymethyl derivative reacts with DNA togive both O⁶-carboxymethyl-2'-deoxyguanosine (O⁶-CMdGuo) and O⁶-methyl-2'-deoxyguanosine(O⁶-MedGuo) [Shuker, D. E. G., and Margison, G. P. (1997) Cancer Res. 57, 366-369] hasbeen confirmed using a range of nitrosated glycine derivatives [N-acetyl-N'-nitroso-N'-prolylglycine (APNG), azaserine (AS), and potassium diazoacetate (KDA)]. In addition,mesyloxyacetic acid (MAA) was also found to give both O⁶-adducts in DNA. O⁶-CMdGuo andO⁶-MedGuo were assessed in enzymatic hydrolysates of treated calf thymus DNA using acombined immunoaffinity/HPLC/fluorescence procedure. The ratio of O⁶-CMdGuo to O⁶-MedGuovaried somewhat between the different compounds with APNG giving the most methylation(O⁶-CM:O⁶-Me ratio of 10) and AS the least (39), with KDA and MAA giving intermediateamounts (16 and 18, respectively). The formation of O⁶-MedGuo by the four compounds probablyarises through decarboxylation at various stages in the decomposition pathways, but the exactmechanisms remain to be clarified. The formation of O⁶-MedGuo from reactions of nitrosatedglycine derivatives with DNA in vitro may explain the frequent detection of this adduct inhuman gastrointestinal DNA, as nitrosation of dietary glycine may occur. O⁶-CMdGuo is likelyto be a useful biomarker of this pathway in vivo and has been detected in human tissues.