Application of the change in partition coefficient with pH to the structure determination of alkyl substituted guanosines

Moore, Patrick D.; Koreeda, Masato

doi:10.1016/0006-291x(76)90729-4

Cited by 23 publications

(11 citation statements)

References 9 publications

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“…Resonances were also detected that could be assigned to H8 and Hi of deoxyguanosine, plus two additional signals that were ascribed to a novel hydrazo linkage. Finally, the adduct had both acidic and basic pka's, as determined by pH-dependent 127 partitioning experiments (23), which was consistent with the proposed deoxyguanosine substitution.…”

Section: Resultssupporting

confidence: 74%

“…The adducts were then identified through high pressure liquid chromatographic comparison to standards synthesized by reacting the respective N-hydroxyarylamine with DNA at acidic pH. In instances where there was sufficient radioactivity, the identity of the individual adducts was confirmed through application of the pH-dependent partitioning technique of Moore and Koreeda (23).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

Beland¹,

Beranek²,

Dooley³

et al. 1983

Environ Health Perspect

176

126

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Hepatic N-oxidation, followed by N-glucuronidation, has been proposed as a route of metabolic activation for arylamine bladder carcinogens. It is postulated that the N-glucuronides are transported to the bladder lumen where they are hydrolyzed under slightly acidic conditions to release directacting carcinogenic and mutagenic N-hydroxyarylamines. In this study, 4-aminobiphenyl (ABP), 1-naphthylamine (1-NA), 2-naphthylamine (2-NA), 2-acetylaminofluorene (AAF), 4-nitrobiphenyl (NBP), benzidine (BZ), and N-acetylbenzidine (ABZ) were administered to male beagle dogs (60 mmole/kg), and the bladder epithelium DNA adducts were quantified at various times after treatment. At 24-48 hr after administration, the order of binding to bladder epithelium DNA was: ABP >> AAF > NBP 2-NA-BZ ABZ>> 1-NA. The level of DNA modification by ABP remained constant for 7 days, whereas 2-NA and AAF residues decreased by 35% and 80%, respectively. The extent and relative persistence of total DNA binding correlated with the compounds' ability to induce bladder tumors in dogs. ABP, AAF, NBP, 2-NA and ABZ administration resulted in DNA binding sufficient for adduct analysis. Enzymatic hydrolysis of the DNA and examination of the adducts by high pressure liquid chromatography indicated that arylamine substitution at C8 of deoxyguanosine was the dominant product. Additional adducts were detected in animals treated with ABP, NBP, and 2-NA. Furthermore, the profiles of adducts obtained in vivo were remarkably similar to the profiles obtained when the N-hydroxy arylamine metabolites of these carcinogens were reacted with DNA in vitro at pH 5.0. To evaluate the mutagenic potential of these arylamine-DNA adducts, Salmonella typhimurium strains TA 1535 and TA 1538 were incubated with N-hydroxy-2-NA, N-hydroxy-2-aminofluorene (AF), N-hydroxy-ABP, and N-hydroxy-ABZ and the resulting DNA adducts and reversions were quantified. Arylamine-C8-deoxyguanosine substitution was correlated with frameshift reversions induced by these agents, with the lesions showing a relative order of mutagenic efficiency of ABZ>AF-2-NA>ABP. These data suggest that mutagenic N-hydroxyarylamines may be ultimate carcinogens for the bladder epithelium. Furthermore, if one assumes that a mutagenic lesion is important for tumor initiation, then C8-deoxyguanosine substitution by these compounds may be significant for urinary bladder carcinogenesis.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

Beland¹,

Beranek²,

Dooley³

et al. 1983

Environ Health Perspect

176

126

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“…Each radioactive peak showed a change in partition coefficient (an indication of ionization) in the regionpH 9.0 to 11.0 (Fig. 3), providing evidence that they are indeed guanosine adducts (12). Furthermore, acid hydrolysis of these in vivo products produced radioactive products coeluting with the tetraols from 1 and 2.…”

mentioning

confidence: 89%

Binding of Nenzo[ a ]pyrene 7,8-Diol-9,10-Epoxides to DNA, RNA, and Protein of Mouse Skin Occurs with High Stereoselectivity

Koreeda

Moore

Wislocki

et al. 1978

Science

Self Cite

267

103

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The formation, stereostructure, and cellular reactions of the 7,8-diol-9,10-epoxide metabolites of the carcinogen benzo[a]pyrene have been examined after topical application of benzo[a]pyrene to the skin of mice. In this known target tissue, polymer adducts from diastereomeric diol epoxides, (+)-(7S, 8R, 9R, 10R) and (+)-(7R, 8S, 9R, 10R), were formed stereospecifically from their corresponding 7,8-dihydrodiols. Both diol epoxides bind with proteins, RNA, and DNA in vivo. For the nucleic acids, binding occurs preferentially at the 2-amino group of guanine in cellular RNA and DNA in vivo. Methods for establishing the structure of the cellular adducts as well as the possible biological implications of their formation are discussed.

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“…This product coeluted with either the synthetic dG-C8-AF adduct at 22-24 min or its ring-opened derivative at 10-12 min (24). The product [in either its ring closed or opened configuration (24)] had UV (25) and pH-dependent partitioning spectra (13,18,26) consistent with identification as dG-C8-AF. Two other bands of radioactivity were detected at 18.5 and 41.0 min.…”

Section: Resultsmentioning

confidence: 97%

Aminofluorene-DNA adduct formation in Salmonella typhimurium exposed to the carcinogen N-hydroxy-2-acetylaminofluorene.

Beranek¹,

White²,

Heflich³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The DNA adducts formed during incubation of the hepatocarcinogen N-hydroxy-2-acetylaminofluorene with Salmonella typhimurium tester strain TA1538 were investigated to determine ifthe covalently bound products were identical to those adducts found in rat liver DNA and to establish the biological significance ofthe adducts in a mutational assay. When bacteria were exposed to N-hydroxy-2-acetylaminofluorene in the presence of a 9,000 x g supernatant from a rat liver homogenate (S9), only one adduct was detected. This adduct had chromatographic, pH-dependent partitioning, and UV spectral characteristics identical to those of N-(deoxyguanosin-8-yl)-2-aminofluorene. In the absence of S9 activation the same product was detected, but at a 85-90% lower level, which indicates that S. typhimurium also may be capable ofmetabolizing N-hydroxy-2-acetylaminofluorene to a reactive electrophile. When incubations were conducted with N-hydroxy-2-aminofluorene in the absence of the activation system, N-(deoxyguanosin-8-yl)-2-aminofluorene again was the major adduct. At equimolar concentrations, the aryihydroxylamine was approximately 10 times more efficient than the arylhydroxamic acid in inducing reversions in the bacteria. Comparison of the mutation rate to the level of binding in bacterial DNA gave a linear relationship with a slope of 0.96 and a correlation coefficient of 0.92. These data support previous suggestions that N-hydroxy-2-acetylaminofluorene is deacetylated by rat liver S9 to the ultimate mutagen, N-hydroxy-2-aminofluorene, and also indicate that S. typhimurium can mediate this reaction. The correlation between mutagenicity and the extent of N-(deoxyguanosin-8-yl)-2-aminofluorene adduct formation, coupled with the observation that this adduct is the major DNA adduct found in rat liver in vivo, suggests that N-(deoxyguanosin-8-yl)-2-aminofluorene may be a critical lesion for the initiation of hepatic tumorigenesis.

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Application of the change in partition coefficient with pH to the structure determination of alkyl substituted guanosines

Cited by 23 publications

References 9 publications

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

Binding of Nenzo[ a ]pyrene 7,8-Diol-9,10-Epoxides to DNA, RNA, and Protein of Mouse Skin Occurs with High Stereoselectivity

Aminofluorene-DNA adduct formation in Salmonella typhimurium exposed to the carcinogen N-hydroxy-2-acetylaminofluorene.

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