73100-87-5Relevant academic research and scientific papers
A new LC-MS/MS method for the quantification of endogenous and vinyl chloride-induced 7-(2-oxoethyl)guanine in Sprague-Dawley rats
Mutlu, Esra,Jeong, Yo-Chan,Collins, Leonard B.,Ham, Amy-Joan L.,Upton, Patricia B.,Hatch, Gary,Winsett, Darrell,Evansky, Paul,Swenberg, James A.
, p. 391 - 399 (2012)
Vinyl chloride (VC) is an industrial chemical that is known to be carcinogenic to animals and humans. VC primarily induces hepatic angiosarcomas following high exposures (≥50 ppm). VC is also found in Superfund sites at ppb concentrations as a result of microbial metabolism of trichloroethylene and perchloroethylene. Here, we report a new sensitive LC-MS/MS method to analyze the major DNA adduct formed by VC, 7-(2-oxoethylguanine) (7-OEG). We used this method to analyze tissue DNA from both adult and weanling rats exposed to 1100 ppm [13C2]-VC for 5 days. After neutral thermal hydrolysis, 7-OEG was derivatized with O-t-butyl hydroxylamine to an oxime adduct, followed by (Figure presented) LC-MS/MS analysis. The limit of detection was 1 fmol, and the limit of quantitation was 1.5 fmol on the column. The use of stable isotope VC allowed us to demonstrate for the first time that endogenous 7-OEG was present in tissue DNA. We hypothesized that endogenous 7-OEG was formed from lipid peroxidation and demonstrated the formation of [13C2]-7-OEG from the reaction of calf thymus DNA with [13C18]-ethyl linoleate (EtLa) under peroxidizing conditions. The concentrations of endogenous 7-OEG in liver, lung, kidney, spleen, testis, and brain DNA from adult and weanling rats typically ranged from 1.0 to 10.0 adducts per 106 guanine. The exogenous 7-OEG in liver DNA from adult rats exposed to 1100 ppm [13C2]-VC for 5 days was 104.0 ± 23.0 adducts per 106 guanine (n = 4), while concentrations in other tissues ranged from 1.0 to 39.0 adducts per 10 6 guanine (n = 4). Although endogenous concentrations of 7-OEG in tissues in weanling rats were similar to those of adult rats, exogenous [ 13C2]-7-OEG concentrations were higher in weanlings, averaging 300 adducts per 106 guanine in liver. Studies on the persistence of [13C2]-7-OEG in adult rats sacrificed 2, 4, and 8 weeks postexposure to [13C2]-VC demonstrated a half-life of 7-OEG of 4 days in both liver and lung.
Tandem Mass Spectrometric Approaches for the Analysis of Alkylguanines in Human Urine
Cushnir, J. R.,Naylor, S.,Lamb, J. H.,Farmer, P. B.
, p. 552 - 558 (2007/10/02)
Human exposure to carcinogenic alkylating agents can lead to the formation of covalently bound adducts in DNA, some of which are excreted in urine as alkylated purines following DNA degradation and repair.Tandem mass spectrometric methods have been developed for the qualitative and quantitative determination of such alkylpurines in human urine.Short-chain alkyl- and hydroxyalkylguanines have been synthesized with the substituents at the N-7, O6- and N2-positions of guanine.Examination of the product ion scans of their molecular ions (electron impact (EI) ionization) revealed that the ion at m/z 151, +, was common to all of the alkylguanines studied, with the exception of the methylated analogues.Precursor ion scans of this ion on partially purified human urine extracts showed the presence of several ions (e.g. m/z 179, 195) which were consistent with molecular ions for alkylguanines.The presence of these and other constituents was confirmed by product ion spectra of molecular ions (EI and fast atom bombardement), and by high-performance liquid chromatographic separation prior to tandem mass spectrometry (MS/MS).Evidence was obtained for the presence of N-7-methyl-, N2-methyl, N2-dimethyl-, N2-ethyl- and N-7-(2-hydroxyethyl)guanine.Quantitative methods were established for these five alkylguanines using gas chromatography mass spectrometry (GC/MS) and GC/MS/MS.Deuterated internal standards were synthesized and added to the urine prior to extraction of alkylpurines by Sep-Pak cartridge chromatography.The products were converted into their tert-butyldimethylsilyl derivatives and analysed by selected ion monitoring (SIM) of + or by multiple reaction monitoring (MRM) of the fragmentation M+. -> +.The MRM method yielded values for N-7-methylguanine of 2.57 +/- S.D. 1.32 mg day-1 (n=6), N2-methylguanine of 0.31 +/- 0.10 mg day-1 (n=10) and N2-dimethylguanine of 0.21 +/- 0.23 mg day-1 (n=10).N2-Ethyl- and N-7-(2-hydroxyethyl)guanine could only be detected by SIM at levels of ca. 0.5 and 2 μg day-1, respectively.The MRM analyses, although inherently less sensitive than the SIM analyses, exhibit greater selectivity and consequently fewer contaminant ions.
Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. I. 7-Substituted 6-oxopurines
Piper,Laseter,Montgomery
, p. 357 - 364 (2007/10/02)
Biological evidence indicates that the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) (EC 2.4.2.8) is vital for cell proliferation in malarial parasites but nonessential for mammalian cells. 7-Substituted guanines and hypoxanthines in wh
