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Titolo:
PYRIDYLOXOBUTYLATION OF GUANINE RESIDUES BY CETOXYMETHYL)NITROSAMINO]-1-(3-PYRIDYL)-1-BUTANONE GENERATES SUBSTRATES OF O-6-ALKYLGUANINE-DNAALKYLTRANSFERASE
Autore:
LIU XK; SPRATT TE; MURPHY SE; PETERSON LA;
Indirizzi:
AMER HLTH FDN,DIV CHEM CARCINOGENESIS,1 DANA RD VALHALLA NY 10595 AMER HLTH FDN,DIV CHEM CARCINOGENESIS VALHALLA NY 10595 AMER HLTH FDN,DIV CARCINOGENESIS & MOL EPIDEMIOL VALHALLA NY 10595
Titolo Testata:
Chemical research in toxicology
fascicolo: 6, volume: 9, anno: 1996,
pagine: 949 - 953
SICI:
0893-228X(1996)9:6<949:POGRBC>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
TOBACCO-SPECIFIC NITROSAMINES; RAT-LIVER; DNA ADDUCTS; F344 RATS; CHEMICAL CARCINOGENESIS; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; N'-NITROSONORNICOTINE; PURIFICATION; REPAIR; O(6)-METHYLGUANINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
23
Recensione:
Indirizzi per estratti:
Citazione:
X.K. Liu et al., "PYRIDYLOXOBUTYLATION OF GUANINE RESIDUES BY CETOXYMETHYL)NITROSAMINO]-1-(3-PYRIDYL)-1-BUTANONE GENERATES SUBSTRATES OF O-6-ALKYLGUANINE-DNAALKYLTRANSFERASE", Chemical research in toxicology, 9(6), 1996, pp. 949-953

Abstract

Pyridyloxobutylation of DNA yields adducts that react with O-6-alkylguanine-DNA alkyltransferase (AGT) to prevent the repair of O-6-methylguanine (O-6-mG). The chemical characterization of pyridyloxobutyl adducts has been confounded by their instability under DNA hydrolysis conditions. They decompose to 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) during the chemical or enzymatic hydrolysis of DNA. The goal of these studies was to determine which bases are pyridyloxobutylated to form AGT-reactive adducts. The model pyridyloxobutylating agent, cetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc), was reacted with eitherpoly(dAdT) or poly(dGdC) to generate DNA substrates for reaction withAGT. Only the pyridyloxobutylated poly(dGdC) was able to prevent the ability of partially purified rat liver AGT to repair O-6-mG. These results paralleled those obtained for the corresponding methylated substrates. These studies are consistent with the pyridyloxobutylation of GC base pairs and not AT base pairs in the DNA to generate a substrate for AGT. In order to distinguish between the formation of reactive adducts at C residues versus G residues, two oligomers were designed thatwere complementary to one another. One oligomer contained A, T, and Gresidues, whereas its complement contained T, A, and C residues. Onlythe dG-containing oligomer reacted with NNKOAc to generate an AGT-reactive adduct, again paralleling the results obtained for a methylatingagent; These results demonstrate that pyridyloxobutylation of only guanine residues produces adducts that react with AGT. These AGT-reactive guanine adducts are relatively stable within DNA, with a half-life of 1-2 weeks at 37 degrees C. They represent up to 70% of the total HPB-releasing adducts in the NNKOAc-treated DNA. We postulate that a potential AGT-reactive adduct is an O-6-(pyridyloxobutyl)guanine adduct.

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Documento generato il 13/07/20 alle ore 11:13:24