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Genetic method for pre‐classification of genotoxins into monofunctional or cross‐linking agents
Author(s) -
Vogel Ekkehart W.,
Zijlstra Jaap A.,
Nivard Madeleine J. M.
Publication year - 1993
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.2850210403
Subject(s) - mutagen , biology , chemistry , genetics , computational biology , dna
To characterize environmental carcinogens, there is a need to distinguish monofunctional genotoxic agents from those having cross‐linking potential, because chemicals which can cross‐link DNA are among the most potent carcinogens in rodents [Barbin and Bartsch, 1989] and humans [Allen et al., 1988; Kaldor et al., 1988]. Here we provide a genetic method for a pre‐classification of genotoxins with respect to their functionality—monofunctional versus cross‐linking. The procedure is based on the determination of relative clastogenic efficiency by a two‐endpoint comparison in Drosophila: (i) induction of chromosome loss (CL), (ii) incidence of recessive lethal mutations (RL). Analysis of CL/RL ratios of 53 genotoxins, all mutagens in Drosophila, permitted distinction of 45 into two major categories: (i) 21 monofunctional agents with CL/RL indices generally ≤1; (ii) 24 agents with ratios >2 exhibiting DNA cross‐linking properties. Within the group of monofunctional agents, CL/RL ratios tend to be low for S SN 1 agents, i.e., for N ‐ethyl‐ N ‐nitrosourea, N ‐ethyl‐ N′ ‐nitro‐ N ‐nitrosoguanidine, and for N ‐nitroso‐diethylamine. With cross‐linking agents, the number of reactive groups appeared of minor importance as bi‐, tri‐, and tetrafunctional agents showed no significant differences in their CL/RL indices. Among 8 chemicals which could not be grouped into one of the two categories are two (adriamycin, daunomycin) regarded as intercalating agents. It is concluded that this two‐endpoint analysis in Drosophila has prognostic value and can assist in the characterization of genotoxic agents with unknown mode of action. © 1993 Wiley‐Liss, Inc.