Mechanisms of DNA breaks induction in vivo by 5-azacytidine: paths of micronucleus induction by azaC.
The aim of the present study was to correlate the time-response curves of micronucleated polychromatic erythrocyte (MN-PCE) induction by 5-azacytidine (azaC) with the possible processes involved in DNA break production; this is based on the results previously published by other authors. The MN-PCE induction at two different doses of azaC was determined by sampling blood from the tails of mice before the acute treatment and over nine periods of 8 h each afterwards. Both doses caused two peaks of MN-PCE induction, one at 32 h and another at 48 h, approximately; a shoulder was detected that remained high from 56 h up to the end of the study (72 h). These results suggest that azaC induced DNA breaks and subsequently MN (micronucleus) by three different mechanisms, and in agreement with data in the literature, these could be successively the following: (i) during excision of the large adduct comprising the DNA methyl transferase covalently linked to DNA; (ii) failure of recombination repair or mismatch repair; and (iii) persistent chromosome fragility in G-C rich sites due to DNA demethylation and chromatin decondensation.
Instituto Nacional de Investigaciones Nucleares, AP 18-1027 México, D.F., México. pmr@nuclear.inin.mx
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Morales-Ramírez
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Vallarino-Kelly
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Cruz-Vallejo
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001374:Azacitidine / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D053960:DNA Breaks; D019175:DNA Methylation / Q000187:drug effects; D053843:DNA Mismatch Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004900:Erythroblasts / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015162:Micronucleus Tests; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D004247:DNA; D001374:Azacitidine