GENOTOXICITY OF POTENTIAL METABOLITES OF NITROSCANATE - AN ANTISCHISTOSOMAL DRUG

The potential metabolites of nitroscanate(4-isothiocyanato-4'-nitrodip henyl ether) such as 4-amino-4'-nitrodiphenyl ether (ANDE), 4-acetamid o-4'-nitrodiphenyl ether (AcNDE), 4-acetamido-4'-nitrosodiphenyl ether (4-N = 0), 4-acetamido-4'-hydroxylaminodiphenyl ether (4-NHOH), 4-ace tamido-4'-acetohydroxamicdiphenyl ether [4-N(OH)Ac], 4-acetamido-4'-fo rmohydroxamicdiphenyl ether [4-N(OH)CHO] and 4-acetamido-4'-acetylacet o-hydroxamicdiphenyl ether [4-N(OAc)Ac] were synthesized and investiga ted in the standard Salmonella mutagenicity test using TA98, TA98NR, T A98/1,8-DNP6, TA100 and TA100NR as indicator strains, in the presence and absence of hepatic S9. The relative order of activity among nitro and its reduction products, 4-N = 0 and 4-NHOH in TA98 and TA100 was 4 -N = 0 > 4-NHOH > AcNDE. In nitroreductase deficient strain TA98NR, Ac NDE was inactive, but expressed a slight activity in TA100NR while 4-N = 0 and 4-NHOH showed a large increase in specific activity in both t he strains. In O-acetyltransferase deficient strain TA98/1,8-DNP6, AcN DE was inactive, while 4-N = 0 and 4-NHOH showed a sharp fall in activ ity. The hydroxylamine derived products with an activity order 4-N(OAc )Ac > 4-N(OH)CHO > 4-N(OH)Ac in both TA98 and TA100, showed 3-6 times increase in the specific activity for the latter two compounds in the presence of S9 mix, which was inhibited in the presence of paraoxan, i ndicating N-deacylation as an important metabolic activation pathway. Except the 4-NO in TA100, the observed mutagenicity of nitroscante (NS C) was higher than those of potential metabolites and the nor-isothioc yanato derivative 4'-nitrodiphenyl ether, thereby showing that -NCS fu nction has a potentiating effect on the mutagenicity of this drug.