Rl. Gupta et al., GENOTOXICITY OF POTENTIAL METABOLITES OF NITROSCANATE - AN ANTISCHISTOSOMAL DRUG, Mutation research. Section on environmental mutagenesis and related subjects, 335(3), 1995, pp. 235-243
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.