Mechanisms and biomarkers of genotoxicity. Molecular dosimetry of chemical mutagens.
The relevance of the use of DNA adduct frequencies as a parameter for the extent of mutation induction by monofunctional alkylating agents was investigated in cultured Chinese hamster cells and in rat skin fibroblasts treated in vivo with the test chemicals. The nature of the biologically significant DNA adducts was investigated by DNA sequence analysis of mutations induced at the hypoxanthine-guanine phophoribosyltransferase (hprt) gene. The results show that under conditions where O6-alkylguanine is a persistent DNA lesion more than 50% of the mutations are GC to AT transitions indicating that the frequency of O6-alkylguanine is a good parameter for mutation induction. However, in target cells which are able to remove alkyl groups from the O6 position of guanine, alkylating agents with a low nucleophilic selectivity (e.g. N-ethyl-N-nitrosourea (ENU) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)) exert most of their mutagenic activity most likely via the induction of O2-ethylthymine.
van Zeeland
A A
AA
MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, The Netherlands.
Jansen
J G
JG
de Groot
A
A
van Hees
S
S
van Teijlingen
C M
CM
op het Veld
C W
CW
Zdzienicka
M Z
MZ
Lohman
P H
PH
Vrieling
H
H
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006099:Granuloma / Q000235:genetics; D016296:Mutagenesis / Q000235:genetics*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats
D009153:Mutagens; D004247:DNA