In vitro induction of micronuclei by monofunctional methanesulphonic acid esters: possible role of alkylation mechanisms.
Six monofunctional alkylating methanesulphonates of widely varying structures were investigated in the in vitro micronucleus assay with Syrian hamster embryo fibroblast cells. The results were compared with the alkylating activities measured in the 4-(nitrobenzyl)pyridine test (NBP-test) and the N-methyl mercaptoimidazole (MMI-test) as measures for S(N)2 reactivity as well as in the triflouoroacetic acid (TFA) solvolysis and the hydrolysis reaction as measures for S(N)1 reactivity in order to provide insights into the role of alkylation mechanisms on induction of micronuclei. Moreover we compared the results of micronucleus assay with those of the Ames tests in strain TA 100 and TA1535 and with those of the SOS chromotest with the strains PQ37, PQ243, PM21 and GC 4798. The potency of methanesulphonates to induce micronuclei depended only to a certain degree, on the total alkylating activity (S(N)1 and S(N)2 reactivity). An inverse, significant correlation between the Ames test and the micronucleus assay was observed and an inverse correlation between the micronucleus assay and the SOS chromotest with the different strains. The results indicate that the primary mechanism leading to induction of micronuclei is not O-alkylation in DNA as it is the case in the Ames test with the hisG46 strains TA1535 and TA100 and not N-alkylation as with the SOS chromotest. There is evidence that protein alkylation, e.g. in the spindle apparatus in mitosis is decisive for induction of micronuclei by alkylating compounds. The structurally voluminous methanesulphonates 2-phenyl ethyl methanesulphonate and 1-phenyl-2-propyl methanesulphonate show a clear higher micronuclei inducing potency than the other tested though the bulky methanesulphonates possess a lower total alkylating activity than the others. This effect can be explained by a higher disturbance during mitosis after alkylation of the spindle apparatus with the structurally more bulky methanesulphonates.
Eder
Erwin
E
Department of Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany. eder@toxi.uni-wuerzburg.de
Kütt
Wolfgang
W
Deininger
Christoph
C
D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D000818:Animals; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D005020:Ethyl Methanesulfonate / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005463:Fluoroacetates / Q000378:metabolism; D006868:Hydrolysis; D008698:Mesylates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008713:Methimazole / Q000378:metabolism; D015162:Micronucleus Tests; D008938:Mitosis / Q000187:drug effects*; D011725:Pyridines / Q000378:metabolism; D013014:SOS Response, Genetics / Q000187:drug effects*
D000477:Alkylating Agents; D004952:Esters; D005463:Fluoroacetates; D008698:Mesylates; D011725:Pyridines; C008633:4-(4-nitrobenzyl)pyridine; C045880:methanesulfonic acid; D008713:Methimazole; D004247:DNA; D005020:Ethyl Methanesulfonate; C046861:n-propyl methane sulfonate; C014815:fluoroacetic acid