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Titolo:
Structure-activity analysis of the potentiation by aminothiols of the chromosome-damaging effect of bleomycin in G(0) human lymphocytes
Autore:
Hoffmann, GR; Buccola, J; Merz, MS; Littlefield, LG;
Indirizzi:
Coll Holy Cross, Dept Biol, Worcester, MA 01610 USA Coll Holy Cross Worcester MA USA 01610 Dept Biol, Worcester, MA 01610 USA Oak Ridge Inst Sci & Educ, Basic & Appl Res Program, Oak Ridge, TN USA OakRidge Inst Sci & Educ Oak Ridge TN USA es Program, Oak Ridge, TN USA
Titolo Testata:
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
fascicolo: 2, volume: 37, anno: 2001,
pagine: 117 - 127
SICI:
0893-6692(2001)37:2<117:SAOTPB>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOUBLE-STRAND CLEAVAGE; HAMSTER OVARY CELLS; BLOCK MICRONUCLEUS METHOD; G0 HUMAN-LYMPHOCYTES; V79 CELLS; S-2-(3-AMINOPROPYLAMINO)-ETHYLPHOSPHOROTHIOIC ACID; 2-<(AMINOPROPYL)AMINO> ETHANETHIOL; AEROBIC RADIOPROTECTION; CLASTOGENIC ACTIVITY; REDUCED-GLUTATHIONE;
Keywords:
bleomycin; aminothiols; micronuclei; human lymphocytes; radioprotectors; polyamines; WR-1065;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
79
Recensione:
Indirizzi per estratti:
Indirizzo: Hoffmann, GR Coll Holy Cross, Dept Biol, 1 Coll St, Worcester, MA 01610 USA Coll Holy Cross 1 Coll St Worcester MA USA 01610 MA 01610 USA
Citazione:
G.R. Hoffmann et al., "Structure-activity analysis of the potentiation by aminothiols of the chromosome-damaging effect of bleomycin in G(0) human lymphocytes", ENV MOL MUT, 37(2), 2001, pp. 117-127

Abstract

The radioprotective aminothiols 2-[(aminopropyl)amino] ethanethiol (WR-1065) and cysteamine (CSM) potentiate the induction of chromosomal damage by the radiomimetic compound bleomycin (BLM) in G, human lymphocytes. To investigate the mechanism of potentiation, we measured the clastogenic activity of BLM in the cytokinesis-block micronucleus assay in the presence and absence of amines, thiols, and aminothiols. The hydroxy analog of WR-1065, 2-(3-aminopropylamino) ethanol (WR-OH), potentiates BLM only slightly, indicating the critical nature of the thiol group. As thiols, WR-1065 and CSM may donate electrons for the activation of Fe+2-BLM or for the regeneration of Fe2-BLM From inactive Fe+3-BLM. The amines putrescine, spermidine, and spermine all potentiate BLM, but they are weaker potentiators than the aminothiols, and they are effective only at high concentrations. Their activity, like that of WR-OH, is probably a consequence of conformational alteration of DNA. Dithioerythritol (DTE) and 2-mercaptoethanol (2-ME), thiols lacking anamino group, are less effective potentiators of BLM than are the aminothiols. The thiol group of WR-1065 and CSM is therefore essential, but insufficient, for explaining the strong enhancement of BLM activity. The cationic nature of CSM and WR-1065, conferred by the amino groups, evidently concentrates the active thiol function at the site of BLM action on DNA. As expected on this basis, the diamine WR-1065 is a more effective potentiator of BLMthan is the monoamine CSM, whereas cysteine and N-acetylcysteine (NAC), which lack a net positive charge, potentiate BLM only weakly. These studies suggest that potentiation of the clastogenic action of BLM by aminothiols can be explained by the combination of a thiol-mediated redox mechanism and an amine-mediated targeting of the thiol function to DNA. (C) 2001 Wiley-Liss, Inc.

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Documento generato il 13/07/20 alle ore 06:40:42