Induction by nitriles of sex chromosome aneuploidy: tests of mechanism.
Genetic and biochemical assays were conducted to determine if nitrile induced adult paralysis and germline aneuploidy in female Drosophila melanogaster requires a biochemical activation mechanism which results in the release of free cyanide. Two nitriles predicted to differ substantially in their susceptibility to enzymatic cyanide release were found to be equally effective inducers of aneuploidy. Regardless of differences in chemical structure, nitriles seem to be affecting a common cellular target as judged by the lack of synergistic effects when two nitriles are presented simultaneously. Mitochondrial respiration was not inhibited by acetonitrile under conditions in which sodium cyanide completely blocked respiration. A sensitive luciferase enzyme inhibition assay suggests that some, but not all, nitriles may affect hydrophobic protein interactions. These results suggest that there is no single biochemical mechanism by which all nitriles induce aneuploidy, although the cellular target disrupted is probably the same for each chemical. The implications of these findings for structural alert based pre-screening of mutagens are discussed.
Osgood
C J
CJ
Dept. of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA.
Cyr
K
K
D000097:Acetonitriles / Q000633:toxicity; D000782:Aneuploidy; D000818:Animals; D001711:Biotransformation; D003486:Cyanides / Q000378:metabolism / Q000633:toxicity; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008156:Luciferases / Q000037:antagonists & inhibitors; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009570:Nitriles / Q000493:pharmacokinetics / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D014960:X Chromosome / Q000187:drug effects* / Q000235:genetics*
D000097:Acetonitriles; D003486:Cyanides; D009570:Nitriles; C006725:benzyl cyanide; C014356:benzonitrile; D008156:Luciferases; C032159:acetonitrile