Pyridyloxobutyl Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine Is Present in 4-(Acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone-Treated DNA and Is a Substrate for O6
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- 作者：Lijuan Wang ; Thomas E. Spratt ; Xiao-Keng Liu ; Stephen S. Hecht ; Anthony E. Pegg ; and Lisa A. Peterson
- 刊名：Chemical Research in Toxicology
- 出版年：1997
- 出版时间：May 1997
- 年：1997
- 卷：10
- 期：5
- 页码：562 - 567
- 全文大小：210K
- 年卷期：v.10,no.5(May 1997)
- ISSN：1520-5010
文摘
The lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) is activated toreactive metabolites that methylate or pyridyloxobutylate DNA.Previous studies demonstratedthat pyridyloxobutylated DNA interferes with the repair ofO6-methylguanine (O6-mG)by O6-alkylguanine-DNA alkyltransferase (AGT). The AGT reactivity ofpyridyloxobutylated DNAwas attributed to (pyridyloxobutyl)guanine adducts. Onepotential AGT substrate adduct, 2'-deoxy-O6-[4-oxo-4-(3-pyridyl)butyl]guanosine(O6-pobdG), was prepared. This adduct wasstableat pH 7.0 for greater than 13 days and to neutral thermal hydrolysisconditions (pH 7.0, 100
C, 30 min). Under mild acid hydrolysis conditions (0.1 N HCl,80 C), O6-pobdG wasdepurinated to yieldO6-[4-oxo-4-(3-pyridyl)butyl]guanine(O6-pobG). O6-pobdGwas hydrolyzedto 4-hydroxy-1-(3-pyridyl)-1-butanone and guanine under strong acidhydrolysis conditions (0.8N HCl, 80 C). O6-pobG was detected in0.1 N HCl hydrolysates of DNA alkylated with themodel pyridyloxobutylating agent4-(acetoxymethylnitrosamino)-1-(3-[5-3H]pyridyl)-1-butanone([5-3H]NNKOAc). When[5-3H]NNKOAc-treated DNA was incubated with eitherrat liver orrecombinant human AGT, O6-pobG was removed,presumably a result of transfer of thepyridyloxobutyl group from the O6-position ofguanine to AGT's active site.
C, 30 min). Under mild acid hydrolysis conditions (0.1 N HCl,80 C), O6-pobdG wasdepurinated to yieldO6-[4-oxo-4-(3-pyridyl)butyl]guanine(O6-pobG). O6-pobdGwas hydrolyzedto 4-hydroxy-1-(3-pyridyl)-1-butanone and guanine under strong acidhydrolysis conditions (0.8N HCl, 80 C). O6-pobG was detected in0.1 N HCl hydrolysates of DNA alkylated with themodel pyridyloxobutylating agent4-(acetoxymethylnitrosamino)-1-(3-[5-3H]pyridyl)-1-butanone([5-3H]NNKOAc). When[5-3H]NNKOAc-treated DNA was incubated with eitherrat liver orrecombinant human AGT, O6-pobG was removed,presumably a result of transfer of thepyridyloxobutyl group from the O6-position ofguanine to AGT's active site.