Genotoxicity of potential metabolites of nitroscanate--an antischistosomal drug.
The potential metabolites of nitroscanate(4-isothiocyanato-4'-nitrodiphenyl ether) such as 4-amino-4'-nitrodiphenyl ether (ANDE), 4-acetamido-4'-nitrodiphenyl ether (AcNDE), 4-acetamido-4'-nitrosodiphenyl ether (4-N = 0), 4-acetamido-4'-hydroxylaminodiphenyl ether (4-NHOH), 4-acetamido-4'-acetohydroxamicdiphenyl ether [4-N(OH)Ac], 4-acetamido-4'-formohydroxamicdiphenyl ether [4-N(OH)CHO] and 4-acetamido-4'-acetylaceto-hydroxamicdiphenyl ether [4-N(OAc)Ac] were synthesized and investigated in the standard Salmonella mutagenicity test using TA98, TA98NR, TA98/1,8-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, AcNDE 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 the strains. In O-acetyltransferase deficient strain TA98/1,8-DNP6, AcNDE was inactive, while 4-N = O and 4-NHOH showed a sharp fall in activity. 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, indicating N-deacylation as an important metabolic activation pathway. Except the 4-NO in TA100, the observed mutagenicity of nitroscante (NSC) was higher than those of potential metabolites and the nor-isothiocyanato derivative 4'-nitrodiphenyl ether, thereby showing that -NCS function has a potentiating effect on the mutagenicity of this drug.
Gupta
R L
RL
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Kaur
I P
IP
Juneja
T R
TR
D000818:Animals; D000923:Anticestodal Agents / Q000633:toxicity*; D001711:Biotransformation; D015195:Drug Design; D008099:Liver / Q000378:metabolism; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D010647:Phenyl Ethers / Q000378:metabolism / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013861:Thiocyanates / Q000378:metabolism / Q000633:toxicity*
D000923:Anticestodal Agents; D009153:Mutagens; D010647:Phenyl Ethers; D013861:Thiocyanates; C011042:nitroscanate