DNA sequence analysis of methylene chloride-induced HPRT mutations in Chinese hamster ovary cells: comparison with the mutation spectrum obtained for 1, 2-dibromoethane and formaldehyde

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Abstract
Glutathione-S-transferase-mediated metabolism of methyl-ene chloride (MC) generates S-chloromethylglutathione, which has the potential to react with DNA, and formaldehyde, which is a known mutagen. MC-induced mutations in the HPRT gene of Chinese hamster ovary cells have been sequenced and compared with the mutations induced by 1, 2-dibromoethane (1, 2-DBE), which is known to act through a glutathione conjugate, and formaldehyde. All three compounds induced primarily point mutations, with a small number of insertion and deletion events. The most common point mutations induced by MC were GC→AT transitions (4/8), with two GC→CG transversions and two AT-→TA transversions. This pattern of mutations showed greater similarity with 1, 2-DBE, where the dominant point mutations were GC→AT transitions (7/9), than formaldehyde, where all mutations were single base transversions and 5/6 occurred from AT base pairs. The mutation sequence results for MC suggest that S-chloromethylglutathione plays a major role in MC mutagenesis, with only a limited contribution from formaldehyde. The involvement of a glutathione (GSH) conjugate in MC mutagenicity would be analogous to the well-characterized pathway of activation of 1, 2-DBE.

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