title: International Commission for Protection Against Environmental Mutagens and Carcinogens. The subtlety of alkylating agents in reactions with biological macromolecules.
abstract: Genotoxic agents known to modify DNA by alkylation reactions (alkylating agents, AAs), either directly or after metabolic conversion to ultimately reactive intermediates, by no means represent a homogeneous class. For instance, their effectiveness for genotoxic damage, when expressed as the number of events (e.g., mutations) per unit exposure dose, varies over a more than 1-million-fold range in dose. Despite the multiplicity of chemical and biological processes involved between DNA adduct formation and expression of genotoxic damage, the principal aims of studies on structure-activity relationships (SARs) are to (a) dissect the multi-step process of genetic damage formation into its most essential components, (b) use SARs for making predictions and, at a later step (c) as a basis for regulatory measures. The analytical tools available for such a comprehensive analysis in eukaryotic systems include determination of multiple genetic endpoints: molecular mutation spectra, relative clastogenicity (clastogenic events in relation to forward mutation induction) and the quantitative measure of enhanced mutagenicity in repair-deficient conditions. The genetic activity profiles obtained in this way can then be compared with fundamental physico-chemical properties of the AAs under consideration (such as Swain-Scott's s value, a useful indicator of the selectivity of an AA in its reactions with nucleophiles of distinct nucleophilic strength n in DNA, RNA and proteins), their functionality (monofunctional versus cross-linking) and their tumorigenic potency (TD50s compared with measures of initial DNA interaction, i.e., O6-/N7-alkylguanine ratios, s values or the covalent binding index determined in the liver in vivo). The combination of these different methods revealed that carcinogenic potencies of AAs in rodents vary over a 10,000-fold range in dose, with the extremes having the following characteristics: (i) Chemicals of a relatively "high carcinogenic potency", as indicated by a low TD50 in rodents, either have low nucleophilic selectivity (and therefore mainly act through O-alkylation in DNA) or are capable of cross-linking DNA. The monofunctional members of this group, typified by N-ethyl-N-nitrosourea, are active in both spermatogonia and post-spermatogonial stages in the mouse and in Drosophila. Cross-linking agents also have a low TD50 value in rodents but are expected generally not to display genetic action in premeiotic stages (exceptions mitomycin C and chlorambucil). (ii) A relatively low carcinogenic potential is associated with AAs of high Swain-Scott s values, typified by trimethyl phosphate, epichlorohydrin or methyl methanesulphonate.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratory, Leiden, The Netherlands.
authors.forename: E W
authors.initials: EW
authors.lastname: Vogel
authors.forename: M J
authors.initials: MJ
authors.lastname: Nivard
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000478:Alkylation; D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D046911:Macromolecular Substances; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D012377:Rodentia; D013329:Structure-Activity Relationship
chemical_list: D000477:Alkylating Agents; D002273:Carcinogens; D003432:Cross-Linking Reagents; D046911:Macromolecular Substances; D009153:Mutagens; D004247:DNA