Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated three different enzymes, each of which splits the glycosidic bonds of normal deoxyribonucleosides, for their ability to cleave acid-sensitive carcinogen-DNA adducts: Leishmania donovani purine deoxyribonucleosidase; Lactobacillus helveticus trans-N-deoxyribosylase; and purine nucleoside phosphorylase. Twenty-eight substrates were assayed using one or more of the enzymes, monitoring free base formation by reverse-phase HPLC and a diode array detector. Products were characterized by their retention times and UV spectra. The deoxyribonucleosidase showed the broadest specificity: substrates cleaved by either the trans-N-deoxyribosylase or the phosphorylase were hydrolyzed by the deoxyribonucleosidase. O6- and N2-alkyldeoxyguanosine, N6-alkyl deoxyadenosine and several cyclic adducts were all hydrolyzed by the deoxyribonucleosidase. None of these enzymes cleaved three bulkier adducts; N2-, N6- and C-8 derivatives of benzo[a]pyrene, benzo[c]phenanthrene and N-acetoxy-2-acetylaminofluorene, respectively. Only the deoxyribonucleosidase hydrolyzed O6-methyldeoxyguanosine while both the deoxyribonucleosidase and trans-N-deoxyribosylase cleaved N6-methyl deoxyadenosine. These enzymes, especially the deoxyribonucleosidase, provide mild ways to release the carcinogen-modified base from deoxyribose and will be useful in DNA adducts analysis.
Carcinogenesis 1991 Jun
PMID:Hydrolysis of carcinogen--DNA adducts by three classes of deoxyribonucleosidase to their corresponding bases. 204 94

Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a phosphate analogue, its potency in vivo appears to be enhanced by reduction to arsenite. To understand the relative importance of this reduction, which is critical in evaluating the responsiveness of cell culture models to the different oxidation states and thus to elucidating the mechanism of arsenic action, present work has correlated the extent of reduction with biological activity in human keratinocytes. The results show that at biologically relevant concentrations, arsenate reduction to appreciable levels required several days, helping rationalize a previous empirical observation that it was approximately one-third as potent as arsenite. The relatively low conversion rate also emphasizes a limitation of culture; arsenate was nearly as efficacious as arsenite, but the time required for it to reach maximal effect exceeded ordinary medium change intervals. In keratinocytes, an important role for purine nucleoside phosphorylase in the reduction could not be demonstrated, indicating that another pathway is dominant in this cell type. Methylation of inorganic arsenic, uptake of methylated forms, and their reduction were all very slow. These findings suggest that the reduced methylated forms have only a small contribution to skin carcinogenesis unless they are supplied through the circulation. In parallel experiments, trivalent antimony was similar to arsenite in potency and efficacy, whereas pentavalent antimony was virtually without biological effect. Conversion of antimony in the pentavalent to the trivalent oxidation state was not detectable in keratinocytes. These findings emphasize the importance of intracellular reduction of the metalloids for biological effects.
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PMID:Biological activity of inorganic arsenic and antimony reflects oxidation state in cultured human keratinocytes. 1468 Mar 77

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) is a well-known marker of oxidative stress. We report a mechanistic analysis of several pathways by which 8-oxodG is converted to nucleotide triphosphates and incorporated into both DNA and RNA. Exposure of MCF-7 cells to [(14)C]8-oxodG combined with specific inhibitors of several nucleotide salvage enzymes followed with accelerator mass spectrometry provided precise quantitation of the resulting radiocarbon-labeled species. Concentrations of exogenously dosed nucleobase in RNA reached one per 10(6) nucleotides, 5-6-fold higher than the maximum observed in DNA. Radiocarbon incorporation into DNA and RNA was abrogated by Immucillin H, an inhibitor of human purine nucleoside phosphorylase (PNP). Inhibition of ribonucleotide reductase (RR) decreased the radiocarbon content of the DNA, but not in RNA, indicating an important role for RR in the formation of 8-oxodG-derived deoxyribonucleotides. Inhibition of deoxycytidine kinase had little effect on radiocarbon incorporation in DNA, which is in contrast to the known ability of mammalian cells to phosphorylate dG. Our data indicate that PNP and RR enable nucleotide salvage of 8-oxodG in MCF-7 cells, a previously unrecognized mechanism that may contribute to mutagenesis and carcinogenesis.
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PMID:Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells. 1802 45

Despite some controversy, selenomethionine (SeMet)-mediated protection against colorectal cancer (CRC) might be a very promising non-cytotoxic option. However, responsive molecular targets and underlying mechanisms of SeMet-mediated chemoprevention are still unclear. Our aim was to discover new targets of SeMet-mediated chemoprevention in CRC using proteomics analysis. We found dietary SeMet supplementation before carcinoma initiation effectively suppressed polyp incidence and dysplastic lesions without any adverse effects. To determine chemopreventive targets of SeMet, we employed two-dimensional gel electrophoresis-based proteomics analysis in CRC mouse model. Pretreatment with SeMet apparently modulated the expression of 30 proteins with functions in major processes like chronic inflammation, oxidative stress and apoptosis as discovered through pathway analysis with Pathway Studio software. We validated four proteins selected from pathway analysis including prohibitin, purine nucleoside phosphorylase, annexin 2 and c-reactive protein by immunohistochemistry. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), a known oxidative stress marker, was decreased by SeMet treatment in CRC mice as seen by immunohistochemistry. Further network analysis was done among these new four validated proteins, 8-OHdG and colorectal cancer. These four proteins found by proteomics analysis might be considered as potential chemopreventive biomarkers of SeMet against colon cancer and can help develop and improve approaches in preventive, therapeutic and prognostic aspects.
Carcinogenesis 2013 Jul
PMID:Discovery of potential targets of selenomethionine-mediated chemoprevention in colorectal carcinoma mouse model using proteomics analysis. 2350 1