Mutagenic activity of isoxazolylnaphthoquinoneimines assayed by micronucleus bone marrow test.
Studies were undertaken to evaluate the ability of various quinoneimines to induce micronuclei in bone marrow cells as a measure of their genotoxicity. Accordingly, 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I), its 2-acetyl derivative (II) and 2-[(5-methyl-3-isoxazolyl)amino]-N-(5-methyl-3-isoxazolyl)-1 ,4- naphthoquinone-4-imine (III), as well as two of their precursors, 2-hydroxynaphthoquinone (NQ-2-OH) and 3,4-dimethyl-5-aminoisoxazole (DMAI) were given by intraperitoneal injection at 5, 50, 100 and 200 mg/Kg doses to S.J.L. Swiss mice with 24 h sampling time. Compounds I and II displayed highly significant differences at 50, 100 and 200 mg/kg doses (p < 0.01) and their mutagenic dose response curves correlated closely with an inverted U-shaped form whose interpretation is still the subject of controversy. NQ-2-OH only produced a significant increase in micronucleus frequency at 50 mg/kg, whereas no mutagenic activity was found for compound III and DMAI at the doses assayed. At 50 mg/kg the order of relative mutagenic potencies was I > II > NQ-2-OH. Mechanisms advanced to explain loss of drug activity at high doses include capture saturation, enzymatic induction during metabolism and participation of an independent defense system.
Sicardi
S M
SM
Laboratorio de Genotoxicidad, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Argentina.
Ferrato
E
E
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007555:Isoxazoles / Q000633:toxicity*; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009153:Mutagens; D009285:Naphthoquinones / Q000633:toxicity*; D012737:Sex Factors
D007555:Isoxazoles; D009153:Mutagens; D009285:Naphthoquinones; C093635:5-amino-3,4-dimethylisoxazole; C005090:lawsone