Susana María Sicardi

Mutagenic activity of isoxazolylnapthoquinoneimines 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.

Evaluación del Potencial Mutagénico de Piroxicam, Meloxicam y Precursores mediante el Ensayo de Micronúcleos in vivo

Mutagenic potential of piroxicam (1), 2-aminopyridine (2), meloxicam (3) and 2-amino-5-methylthiazole (4) has been evaluated using in vivo micronucleus test. Four dose levels for each compound were used and bone marrow cells were examined 24 hours after the administration. In the case of the degradation product of piroxicam (2) only 0.1, 0.3, 1.0 and 5.0 mg/kg were evaluated, because at 50 mg/kg all animals died. The results show that doses applied do not induce a statistical significant increase of the frequency of micronucleated polychromatic erythrocytes. Aniline (5) has been used as positive mutagen reference, showing a positive response to the micronucleous induction at doses of 50mg/kg or superior while no induction occur with lower doses. The structural-mutagenic activity relationship between piroxicam and aniline could not been established.