Guanosine adducts of the potent bacterial drinking water mutagen MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone]

L. Kronberg, PhD a, T. Munter, PhD a, M. Lloveras, PhD b, F. Le Curieux, PhD c, and A. Messeguer, PhD b

a Department of Organic Chemistry, Åbo Akademi University, Åbo/Turku, Finland, b Department of Biological Organic Chemistry, CID CSIC, Barcelona, Spain, c Laboratory of Toxicology, Institut Pasteur de Lille, Lille, France

AIM. The potent direct acting bacterial mutagen MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] is a by-product of chlorine disinfection of drinking water. Several studies on the genotoxicity of MX have indicated that the compound forms adducts with the nucleoside guanosine. The aim of our work is the structural determination of adducts formed in reaction of MX with guanosine. METHODS. MX or its brominated analogues, BMX-1, BMX-2 and BMX-3, were reacted with guanosine at neutral or near neutral conditions at 37 oC. The adduct formation was followed by HPLC analyses of the reaction mixtures . The formed adducts were isolated using semi-preparative chromatography. The structures were elucidated by UV and NMR spectroscopy and mass spectrometry. RESULTS. Two major adducts were found to be formed. In one of the adducts, a formyl substituted etheno bridge has been incorporated between N-1 and N2 of guanosine. The spectral data of the other adduct show that adduction has taken place at the imidazole ring. The preliminary work on the structural characterization of this adduct indicates a structure consisting of a substituted propenone bridge between N-7 and C-8. CONCLUSIONS. The study has demonstrated that MX and its brominated analogues form stable adducts with guanosine and thus confirms the findings of mutational spectra and DNA sequence analyses of MX induced lesions.

KEY WORDS: genotoxicity, disinfection by-product, structural identification.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Environment and Occupation.