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Titolo:
The importance of distinct metabolites of N-nitrosodiethylamine for its invivo mutagenic specificity
Autore:
Sierra, LM; Tosal, L; Nivard, MJM; Comendador, MA; Vogel, EW;
Indirizzi:
Univ Oviedo, Dept Biol Func, Oviedo 33006, Spain Univ Oviedo Oviedo Spain 33006 iedo, Dept Biol Func, Oviedo 33006, Spain Leiden Univ, Ctr Med, Sylvius Labs, MGC,Dept Radiat Genet & Chem Mutagenesis, NL-2300 RA Leiden, Netherlands Leiden Univ Leiden Netherlands NL-2300RA NL-2300 RA Leiden, Netherlands Univ Oviedo, Inst Univ Oncol, Area Genet, Oviedo 33006, Spain Univ OviedoOviedo Spain 33006 iv Oncol, Area Genet, Oviedo 33006, Spain
Titolo Testata:
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
fascicolo: 1-2, volume: 483, anno: 2001,
pagine: 95 - 104
SICI:
1386-1964(20011101)483:1-2<95:TIODMO>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUNCTIONAL ALKYLATING-AGENTS; HIGHER EUKARYOTIC SYSTEMS; INDUCED LIVER-TUMORS; MALE GERM-CELLS; DROSOPHILA-MELANOGASTER; NUCLEOPHILIC SELECTIVITY; VERMILION MUTATIONS; MOLECULAR ANALYSIS; ETHYLATING AGENTS; RAS PROTOONCOGENE;
Keywords:
N-nitrosodiethylamine; metabolism; Drosophila germ cells; mutation spectrum; genetic rearrangements;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Sierra, LM Univ Oviedo, Dept Biol Func, Oviedo 33006, Spain Univ Oviedo Oviedo Spain 33006 Biol Func, Oviedo 33006, Spain
Citazione:
L.M. Sierra et al., "The importance of distinct metabolites of N-nitrosodiethylamine for its invivo mutagenic specificity", MUT RES-F M, 483(1-2), 2001, pp. 95-104

Abstract

Although N-nitrosodiethylamine (NDEA) is a potent carcinogen in rodents and a probable human carcinogen, little attempts were made to characterize its mutation spectrum in higher eukaryotes. We have compared forward mutationfrequencies at multiple (700) loci with the mutational spectrum induced atthe vermilion gene of Drosophila, after exposure of post- and pre-meiotic male germ cells to NDEA. Among 30 vermilion mutants collected from post-meiotic stages were 12 G:C --> A:T transitions (40%), 8 A:T --> T:A transversions (27%), and 4 structural rearrangements (13%). The remainder were three A:T --> G:C transitions, two G:C --> C:G transversions and one G:C --> T:A transversion. The results show that although NDEA induces predominantly transitions (40% G:C --> A:T and 10% A:T --> G:C), the frequencies of transversions (37%, of which 27% of A:T --> T:A transversions) and especially of rearrangements (13%) are remarkably high. This mutation spectrum differs significantly from that produced by the direct-ethylating agent N-ethylnitrosourea (ENU), although the relative distribution of ethylated DNA adducts is similar for both carcinogens. These differences, in particular the occurrence of rearrangements, are most likely the result of the requirement of NDEA for bioactivation. Since all four rearrangements were collected from non-metabolizing spermatozoa (or late spermatids), it is hypothesized that they derived from acetaldehyde, a stable metabolite of NDEA. Due to its cytotoxicity, attempts to isolate vermilion mutants from NDEA-exposed pre-meiotic cells were largely unsuccessful, because only two mutants (one A:T G:C transition and one 1 bp insertion) were collected from those stages. Our results show that NDEA is capable of generating carcinogenic lesions other than base pair substitutions. (C) 2001 Elsevier Science B.V. All rights reserved.

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Documento generato il 11/07/20 alle ore 20:59:52