Alkylation of nucleosides and nucleotides by dehydroretronecine; characterization of covalent adducts by liquid secondary ion mass spectrometry

Wickramanayake, Palitha P.; Arbogast, Brian; Buhler, Donald R.; Deinzer, Max L.; Burlingame, Alma L.

doi:10.1021/ja00294a047

Cited by 33 publications

(14 citation statements)

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“…It has long been determined that dehydromonocrotaline, dehydroretrorsine, DHR, and dehydroheliotridine (DHH) can bind to DNA, nucleosides, and nucleotides. ,− These results indicate that DHP ester metabolites could bind with cellular DNA in vivo, resulting in liver tumor initiation mediated by exogenous DNA adduct formation.…”

Section: Current Understanding Of Metabolic Activationmentioning

confidence: 99%

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation

2016

Chem. Res. Toxicol.

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Pyrrolizidine alkaloids (PAs) and PA N-oxides are a class of phytochemical carcinogens contained in over 6000 plant species spread around the world. It has been estimated that approximately half of the 660 PAs and PA N-oxides that have been characterized are cytotoxic, genotoxic, and tumorigenic. It was recently determined that a genotoxic mechanism of liver tumor initiation mediated by PA-derived DNA adducts is a common metabolic activation pathway of a number of PAs. We proposed this set of PA-derived DNA adducts could be a common biological biomarker of PA exposure and a potential biomarker of PA-induced liver tumor formation. We have also found that several reactive secondary pyrrolic metabolites can dissociate and interconvert to other secondary pyrrolic metabolites, resulting in the formation of the same exogenous DNA adducts. This present perspective reports the current progress on these new findings and proposes future research needed for obtaining a greater understanding of the role of this activation pathway and validating the use of this set of PA-derived DNA adducts as a biological biomarker of PA-induced liver tumor initiation.

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Section: Current Understanding Of Metabolic Activationmentioning

confidence: 99%

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation

2016

Chem. Res. Toxicol.

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“…While a variety of mass spectrometric techniques have been employed for the characterization of nucleic acid adducts (7), it has been fast atom bombardment (FAB) ionization, combined with tandem mass spectrometric methods, which has been used most widely for structural characterization of intact polycyclic aromatic hydrocarbons (PAH)-deoxynucleoside adducts and similar compounds (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In studies where high-sensitivity static FAB characterization has been emphasized, chemical derivatization of isolated materials has typically been employed (10,11).…”

Section: Introductionmentioning

confidence: 99%

Application of capillary liquid chromatography coupled with tandem mass spectrometric methods to the rapid screening of adducts formed by the reaction of N-acetoxy-N-acetyl-2-aminofluorene with calf DNA

Wolf

Vouros²

1994

Chem. Res. Toxicol.

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Capillary liquid chromatography-continuous-flow fast atom bombardment mass spectrometry is applied to the detection of deoxynucleoside adducts of N-acetoxy-N-acetyl-2-aminofluorene. In such a configuration, normal scan and tandem mass spectrometric techniques are shown to provide useful structural information for an N-acetyl-N-(deoxyguanosin-8-yl)-2-aminofluorene adduct standard for low- nanogram (low-picomole) amounts sampled. In addition, multiple reaction monitoring gives limits of detection below 25 pg (50 fmol) for this adduct, suggesting the potential for routine screening of intact deoxynucleoside adducts formed below the 1:10(6) level from as little as 1 mg of DNA. When applied to the analysis of the products of an in vitro reaction of calf thymus DNA with N-acetoxy-N-acetyl-2-aminofluorene, these techniques are readily able to detect and supply structural data for the N2 and C8 deoxyguanosine adducts formed.

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“…These unstable dehydroalkaloids are potent electrophiles that can either form covalent adducts with cellular constituents (Niwa et al 1991) or can undergo rapid hydrolysis to the more stable DHP and the corresponding neck acid (Mattocks 1986, Kedzierski andBuhler 1985). Although D H P is less reactive than the dehydroalkaloids, the chemically isolated R-enantiomer of DHP, dehydroretronecine, (R)-DHP, is also capable of alkylating cellular macromolecules, including DNA (White and Mattocks 1972, Robertson 1982, Mattocks and Bird 1983 and has been shown to be carcinogenic .…”

Section: Introductionmentioning

confidence: 99%

“…Dehydromonocrotaline (Niwa et al 1991) and (R)-DHP (Wickramanayake et al 1985) alkylate nucleosides and nucleotides in vitro while (R)-DHP binds to protein both in oitro and in oivo (Hsu et al ,1976. (R)-DHP has also been found to react chemically (in vitro) under acidic conditions with cysteine (CYS) and glutathione (GSH) to form DHP-CYS and DHP-GSH adducts, probably by reactionat the C-7 hydroxyl (Robertson et al 1977).…”

Section: Introductionmentioning

confidence: 99%

Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine

et al. 1992

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1. Pyrrolizidine alkaloids (PAs) are metabolized primarily to putative dehydroalkaloid (PA pyrrole) metabolites and to PA N-oxide by rat liver microsomal monooxygenases. 2. The dehydroalkaloids are highly reactive and either bind covalentely to tissue nucleophiles or are hydrolysed to the more stable pyrrole, (R,S)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), and the corresponding necic acid. 3. Addition of glutathione (GSH 1 mM) to incubation mixtures containing rat liver microsomes and the PA senecionine (SN), resulted in the formation of a conjugate of DHP with GSH. 5. The mass spectrum of this DHP-GSH conjugate was identical to that of the chemically-synthesized dehydroretronecine (the R enantiomer of the racemic DHP) and GSH. 6. Only negligible amounts of DHP-GSH conjugate were formed when DHP itself was incubated with GSH at physiological pH. 7. These findings provide strong evidence for the microsomal conversion of SN to a highly reactive metabolite, presumably dehydrosenecionine, which then reacts with GSH to form the DHP-GSH conjugate. 8. It is likely that a similar mechanism is responsible in vivo for the formation of GSH conjugates of DHP from SN and other PAs.

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Alkylation of nucleosides and nucleotides by dehydroretronecine; characterization of covalent adducts by liquid secondary ion mass spectrometry

Cited by 33 publications

References 0 publications

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation

Application of capillary liquid chromatography coupled with tandem mass spectrometric methods to the rapid screening of adducts formed by the reaction of N-acetoxy-N-acetyl-2-aminofluorene with calf DNA

Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine

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