Moclobemide and selegeline in the treatment of depression in Parkinson's diseaseMonoamine oxidase (MAO) is the predominant enzyme implied in the catabolism of the monoamines dopamine, noradrenaline, and serotonin.1 Dopamine is a substrate for both isoforms of MAO: the extraneuronal MAO-B; and MAO-A which is found both extraneuronally and intraneuronally.

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The nature of mutations induced by 1,2-dibromoethane (DBE) at the hprt (hypoxanthine-guanine phosphoribosyl-transferase) gene was analysed in Chinese hamster ovary (CHO-9) cells. Molecular characterization of 36 hprt mutants at the cDNA level yielded 19 GC-->AT transitions, two AT-->CG transversions, three frameshift mutations, two identical small deletions and 10 exon deletions. Further analysis of the deletion mutants by amplification of specific exons from genomic DNA showed two more GC-->AT transitions at splice sites and an approximately 70 bp deletion. Assuming that the S-[2-(N7-guanyl)ethyl]glutathione adduct is responsible for the GC-->AT transitions, 90% of the affected guanines were located in the non-transcribed strand of the hprt gene, suggesting a strand bias in repair of this adduct. Nearest neighbour analysis of induced GC-->AT transitions indicates a preference for a 5'-PyPuG DNA sequence, i.e. 15/21 mutated guanines were located in either a TGG or a CAG DNA sequence. These molecular data on DBE-induced mutations showed similar features as data from a study by Graves et al. (Mutagenesis, 11, 229-233, 1996) in which they analyzed 13 hprt mutants induced by DBE in CHO-K1 cells. Six of the seven GC-->AT mutations were on positions mutated more than once among the 36 hprt mutants in the present study. The combined findings suggest that some positions seem to be hot spots for DBE-induced mutations. Concerning the relevance of these in vitro studies for germ cell mutagenesis the conclusion may be that these data lend further support to the view that mutation spectra derived from in vitro systems have little predictive value for the nature of mutations induced in post-meiotic germ cells in vivo, as demonstrated for other alkylating agents in both Drosophila and mice.

DNA sequence changes produced by 1,2-dibromoethane (DBE), 1,2-dichloroethane (DCE) and 1-bromo-2-chloroethane (BCE) were analyzed using the vermilion locus of Drosophila melanogaster. Under excision repair proficient (exr+) conditions (mutagenized exr+ males mated with exr+ females) all mutants isolated from the first generation (F1) after DBE and DCE exposure represented DNA rearrangements (multi-locus deletions, small deletions with tandem repeats, duplicate insertions). By contrast, mutants expressing a vermilion phenotype only in the F2 (F1 mosaics) all carried single bp changes. When exr+ males, after exposure to DBE, were mated to excision repair deficient (exr-) mus 201 females 11 of 14 mutational events isolated from either F1 or F2 progeny were single bp changes. In general the mutation spectra for the three dihaloalkanes were similar to the spectrum obtained at the same locus for the direct-acting monofunctional agent methylmethanesulfonate (MMS). The data lend support to the conclusions that these 1,2-dihaloalkanes are genotoxic through modification at ring nitrogens in DNA, primarily at the N7 of guanine and, to a lesser extent, at the N1 of adenine. These N-adducts could be directly miscoding. However, more important for the mutagenic action of the chemicals seems to be the formation of non-coding lesions and/or misrepair.