title: Quantitative assessment of the dose-response of alkylating agents in DNA repair proficient and deficient ames tester strains.
abstract: Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even "thresholded" dose-response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium: the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada-), YG7104 (Ogt-/Ada+) and YG7108 (Ogt-/Ada-). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose-response curves were statistically fitted by the PROAST benchmark dose model and the Lutz-Lutz "hockeystick" model. These dose-response curves suggest efficient DNA-repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl-transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds.
authors.affiliation: pRED, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Leilei
authors.initials: L
authors.lastname: Tang
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeller
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D008741:Methyl Methanesulfonate / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D008780:Methyltransferases / Q000235:genetics; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013045:Species Specificity; D000077204:Temozolomide
chemical_list: D000477:Alkylating Agents; D009153:Mutagens; D008770:Methylnitrosourea; D003606:Dacarbazine; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D008780:Methyltransferases; D004265:DNA Helicases; D000077204:Temozolomide
keywords: Ames test; DNA repair; PROAST; dose-response relationship