DNA-DAMAGE AND REPAIR IN MUTAGENESIS AND CARCINOGENESIS - IMPLICATIONS OF STRUCTURE-ACTIVITY-RELATIONSHIPS FOR CROSS-SPECIES EXTRAPOLATION

Citation
Ew. Vogel et al., DNA-DAMAGE AND REPAIR IN MUTAGENESIS AND CARCINOGENESIS - IMPLICATIONS OF STRUCTURE-ACTIVITY-RELATIONSHIPS FOR CROSS-SPECIES EXTRAPOLATION, Mutation research, 353(1-2), 1996, pp. 177-218
Citations number
140
Categorie Soggetti
Genetics & Heredity",Biology,"Biothechnology & Applied Migrobiology
Journal title
ISSN journal
00275107
Volume
353
Issue
1-2
Year of publication
1996
Pages
177 - 218
Database
ISI
SICI code
0027-5107(1996)353:1-2<177:DARIMA>2.0.ZU;2-D
Abstract
Previous studies on structure-activity relationships (SARs) between ty pes of DNA modifications and tumour incidence revealed linear positive relationships between the log TD50 estimates and s-values for a serie s of mostly monofunctional alkylating agents. The overall objective of this STEP project was to further elucidate the mechanistic principles underlying these correlations, because detailed knowledge on mechanis ms underlying the formation of genotoxic damage is an absolute necessi ty for establishing guidance values for exposures to genotoxic agents. The analysis included: (1) the re-calculation and further extension o f TD50 values in mmol/kg body weight for chemicals carcinogenic in rod ents. This part further included the checking up data for Swain-Scott s-values and the use of the covalent binding index (CBI); (2) the elab oration of genetic toxicity including an analysis of induced mutation spectra in specific genes at the DNA level, i.e., the vermilion gene o f Drosophila, a plasmid system (pX2 assay) and the HPRT gene in cultur ed mammalian cells (CHO-9); and (3) the measurement of specific DNA al kylation adducts in animal models (mouse, rat, hamster) and mammalian cells in culture. The analysis of mechanisms controlling the expressio n of mammalian DNA repair genes (alkyltransferases, glycosylases) as a function of the cell type, differentiation stage, and cellular microe nvironment in mammalian cells. The 3 classes of genotoxic carcinogens selected for the project were: (1) chemicals forming monoalkyl adducts upon interaction with DNA; (2) genotoxins capable of forming DNA ethe no-adducts; and (3) N-substituted aryl compounds forming covalent addu cts at the C8 position of guanine in DNA. In general, clear SARs and A ARs (activity-activity relationships) between physiochemical parameter s (s-values, O-6/N7-alkylguanine ratios, CBI), carcinogenic potency in rodents and several descriptors of genotoxic activity in germ cells ( mouse, Drosophila) became apparent when the following descriptors were used: TD50 estimates (lifetime doses expressed in mg/kg b.wt. or mmol /kg b.wt.) from cancer bioassays in rodents; the degree of germ-cell s pecificity, i.e., the ability of a genotoxic agent to induce mutations in practically all cell stages of the male germ-cell cycle of Drosoph ila (this project) and the mouse (literature search), as opposed to a more specific response in postmeiotic stages of both species; the M(ex r-)/M(exr+) hypermutability ratio, determined in a repair assay utiliz ing Drosophila germ cells; mutation spectra induced at single loci (th e 7 loci used in the specific-locus test of the mouse (published data) , and the vermilion gene of Drosophila); and doubling doses (DD) in mg /kg (mmol/kg) for specific locus test results on mice. By and large, t he TD50 values, the inverse of which can be considered as measures of carcinogenic potency, were shown to be predictable from knowledge of t he in vivo doses associated with the absorbed amounts of the investiga ted alkylators and with the second-order constant, k(c), reaction at a critical nucleophilic strength, n(c). For alkylating agents k(c) can be expressed as the second-order rate constant for hydrolysis, k(H2O), and the substrate constant s:k(H2O)TD(50) is a function of a certain accumulated degree of alkylation, here given as the (average) daily in crement a(c) for 2 years exposure of the rodents. The T-50 in mmol/kg X day) could then be written: T-fsD(50) = a(c) X lambda/k(H2O) X 10( n)c . s</SUP> This expression would be valid for monofunctional alkyla tors provided the reactive species are uncharged. This is the case for most S(N)2 reagents. Although it appears possible to predict carcinog enic potency from measured in vivo doses and from detailed knowledge o f reaction-kinetic parameter values, it is at present not possible to quantify the uncertainty of such predictions. One main reason for this is the complication due to uneven distribution in the body, with effe cts on the dose in target tissues. The estimation can be improved by c onsidering the distribution of dose in the body. In the present analys is, direct-acting alkylators were studied. It is evident that dosimetr y and reaction-kinetic characterization of genotoxic metabolites would render it possible to predict the potency of precarcinogens as well.