DNA-SEQUENCE ANALYSIS OF METHYLENE CHLORIDE-INDUCED HPRT MUTATIONS INCHINESE-HAMSTER OVARY CELLS - COMPARISON WITH THE MUTATION SPECTRUM OBTAINED FOR 1,2-DIBROMOETHANE AND FORMALDEHYDE

Glutathione-S-transferase-mediated metabolism of methylene chloride (M C) generates S-chloromethylglutathione, which has the potential to rea ct with DNA, and formaldehyde, which is a known mutagen, MC-induced mu tations in the HPRT gene of Chinese hamster ovary cells have been sequ enced and compared with the mutations induced by 1,2-dibromoethane (1, 2-DBE), which is known to act through a glutathione conjugate, and for maldehyde, All three compounds induced primarily point mutations, with a small number of insertion and deletion events, The most common poin t mutations induced by MC were GC-->AT transitions (4/8), with two GC- ->CG transversions and two AT-->TA transversions, This pattern of muta tions showed greater similarity with 1,2-DBE, where the dominant point mutations were GC-->AT transitions (7/9), than formaldehyde, where al l mutations were single base transversions and 5/6 occurred from AT ba se pairs, The mutation sequence results for MC suggest that S-chlorome thylglutathione plays a major role in MC mutagenesis, with only a limi ted contribution from formaldehyde, The involvement of a glutathione ( GSH) conjugate in MC mutagenicity would be analogous to the well-chara cterized pathway of activation of 1,2-DBE.