The mutagenicity of azathioprine in mice, Drosophila melanogaster and Neurospora crassa.
The chemotherapeutic coumpound azathioprine was tested for possible mutagenicity in Swiss Albino mice, Drosophila melanogaster and Neurospora crassa. Utilizing the dominant-lethal assay it was found that acute oral doses of azathioprine (2 times 25 mg/kg body weight), induced dominant-lethal mutations in mouse spermatocytes. Chronic oral doses of azathioprine (2 times 25 mg/kg body weight/week for 10 weeks) resulted in a greater rate of dominant-lethality. This increase was not permanent, and by week 4 of gamete sampling there was no significant increase in dominant-lethal mutations. Histological sections showed that chronic treatment of male mice with azathioprine caused pyknosis of spermatocyte nuclei and depletion of the spermatid population. Both acute and chronic doses of azathioprine caused a temporary reduction in sperm viability. Oral treatment of male Canton-S, D. melanogaster with azathioprine caused an increase in dominant-lethality in broods assumed to correspond to spermatid and spermaotcyte stages. Azathioprine also increased the rate of non-disjunction of the X and Y chromosomes, loss of the long arm of the Y chromosome, and loss of the X or Y chromosome in treated male R(I)2, vf/BsYy+D. melanogaster. Since sex-ratio deviation did not occur in progeny from treated rod-X (yv/B2Yy+) male D. melanogaster, it was concluded that the observed sex-ration deviation in the treated ring-X stock was the result of induced ring-X lethality. Azathioprine induced recessive-lethal mutations in the ad-3 region of a N. crassa heterokaryon. In the host-mediated assay using this same heterokaryon and male Swiss Albino mice as host, the mutagenic activity of azathioprine did not appear to be potentiated or detoxified by the host. The results show that azathioprine has a deleterious effect on reproduction in mice and probably induces mutational events in mice, D. melanogaster and N. crassa.
D000818:Animals; D001379:Azathioprine / Q000008:administration & dosage / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects; D005260:Female; D005799:Genes, Dominant; D005804:Genes, Lethal; D005808:Genes, Recessive; D008297:Male; D008540:Meiosis; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D009492:Neurospora crassa / Q000187:drug effects; D011336:Probability; D012098:Reproduction / Q000187:drug effects*; D012671:Seminiferous Tubules / Q000187:drug effects; D012730:Sex Chromosomes / Q000187:drug effects; D012744:Sex Ratio; D013094:Spermatozoa / Q000187:drug effects
D009153:Mutagens; D001379:Azathioprine