Mutagenicity and induction of sister chromatid exchange by optically active enantiomers of secondary butyl methanesulfonate.
This report describes experiments in which a chiral alkyl methanesulfonate was used to investigate possible mechanisms by which alkylating agents cause their mutagenic, cytotoxic, and clastogenic effects. Optically active enantiomers and the racemic mixture of 2-butyl methanesulfonate (2-BMS) were cytotoxic and mutagenic in Chinese hamster V79 cells and in AS52 cells and mutagenic in Salmonella typhimurium strains TA100 and TA1535 (without the addition of exogenous metabolizing systems). Within the experimental uncertainties, the cytotoxicity and mutagenicity curves were the same for the R and S enantiomers and for the racemic mixture. The 2-BMS isomers were cytotoxic and induced sister chromatid exchanges (SCE) in CHO-K1-BH4 cells. The cytotoxicity curve was similar to that observed with V79 and AS52 cells. The induction of SCE was linear between 1 and 6 mM 2-BMS with no differences discernable between the isomers. The results can be interpreted two ways. The first interpretation is that 2-BMS reacts via a carbocation, and the second interpretation involves an SN2 reaction of 2-BMS with DNA. The latter interpretation suggests that the mechanisms of mutagenesis, cytotoxicity, or the induction of SCE cannot distinguish between small (four-carbon) optically active DNA adducts. We favor the second interpretation because of solvolysis experiments showing the complete inversion of configuration of optically active 2-octyl methanesulfonate (2-OMS, Weiner and Sneen: J American Chemical Society 87:287-291, 1965). While we assume that optically active 2-BMS will react using the same mechanism as chiral 2-OMS, we cannot exclude the possibility that 2-BMS reacts via a carbocation intermediate.
Ball
J C
JC
Scientific Research Laboratory, Ford Motor Co., Dearborn, Michigan 48121.
Salmeen
I T
IT
Morris
S M
SM
D000818:Animals; D002460:Cell Line; D002999:Clone Cells / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D006151:Guanosine / Q000378:metabolism; D008698:Mesylates / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D009152:Mutagenicity Tests; D009154:Mutation; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013237:Stereoisomerism
D008698:Mesylates; D006151:Guanosine; C018011:butyl methanesulfonate; D004247:DNA