DNA-DAMAGING ACTIVITY INVIVO AND BACTERIAL MUTAGENICITY OF 16 HYDRAZINE DERIVATIVES AS RELATED QUANTITATIVELY TO THEIR CARCINOGENICITY

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (4) , 1469-1482
Abstract
Hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, phenylhydrazine, procarbazine, isoniazid, isocarboxazid, nialamide, 2,4-dinitrophenylhydrazine, phenelzine, hydralazine, dihydralazine, carbamylhydrazine, mebanazine, iproniazid and 1-carbamyl-2-phenylhydrazine were tested for DNA-damaging activity by the alkaline elution technique and for mutagenic activity in the Salmonella microsome (Ames) test. The first 9 compounds listed (56%) induced a significant DNA fragmentation in the liver and/or lung of i.p.-treated male Swiss mice. The DNA damaging potency varied over an .apprx. 30-fold range. Thirteen of the first 14 compounds listed (81% of the total), isocarboxazid being inactive, were positive in the Ames test, with a broad range of activity towards the 5 bacterial strains of S. typhimurium used (TA1535, TA100, TA1537, TA1538 and TA98) and of metabolic behavior in the presence of S-9 mix containing rat liver, mouse liver or mouse lung postmitochondrial preparations from Aroclor-treated animals. The mutagenic potency varied over an almost 7000-fold range. For 11 of the 16 hydrazine derivatives tested, homogeneous carcinogenicity data (induction of pulmonary tumors in mice chronically treated p.o. [orally]) were available from literature. Carcinogenic potency varied over an .apprx. 1900-fold range. The 5 most potent carcinogens were all positive in the DNA damage test. Their carcinogenic potency varied over a 130-fold range and their DNA-damaging potency seemed to vary on a more compressed scale, but regression analysis indicated the existence of a strong positive correlation between in vivo DNA-damaging and carcinogenic potencies, while a lack of correlation was found between mutagenic and carcinogenic potencies. There was correlation between DNA-damaging and mutagenic potencies.