Genotoxicity of the anticonvulsant drug phenytoin (PHT): A follow‐up study of PHT‐untreated epileptic patients. II. Mitotic index (MI) and proliferation kinetics

Abstract

The mitotic index and proliferation rate index were investigated to determine the effect of phenytoin (PHT) in cultured blood lymphocytes of epileptics prior to and following administration of PHT over a period of 9 months (grouped in multiples of 3 months) and 40 control subjects (age range 10-30 years). Treatment with PHT brought inhibition of the mitotic index (MI) and proliferation rate index (PRI), which were significantly higher in treated subjects or which were more expressive in treated lymphocytes (P < 0.001) for all the three durations of treatment. In addition, statistically significant heterogeneity of first, second, and third metaphases between the treated, untreated, and control subjects was found. Mean PRI values were used to estimate cell cycle delays, showing the highest effect in treated lymphocytes (P < 0.001). There was no considerable variation between the control and untreated (P > 0.05). The study demonstrates that PHT may be potentially genotoxic and hence the usefulness of MI and PRI in monitoring epileptics on anticonvulsant treatment.

II. An altered proliferation response due to the anticonvulsant phenytoin (PHT) in epileptic patients

“…These results demonstrate that proliferation end points associated with cytogenetic measurements (in Paper I, this issue) are sufficiently sensitive to detect the effects of drugs, which could be genotoxicants. The most pronounced reduction in MI% (by about 1/3) observed at 9 months of PHT-treatment when compared with PHT-untreated and control subjects is similar to the results observed for the subjects [11]. The MI% observed in these treated epileptics was higher than that obtained by Goyle et al [1].…”

“…Anticonvulsant treatment in epileptics has been the subject of numerous studies [1][2][3][4][5][6]. In vivo and in vitro treatments with various anticonvulsants induce chromosomal aberrations [7] and sister chromatid exchanges [5][6][7][8][9][10][11]. MI and PRI are generally used as cytogenetic end points for the detection of the mutagenic effects of anticonvulsants [1,2,[10][11][12].…”

II. An altered proliferation response due to the anticonvulsant phenytoin (PHT) in epileptic patients

“…The most pronounced reduction in MI% (by about 1/3) observed at 9 months of PHT-treatment when compared with PHT-untreated and control subjects is similar to the results observed for the subjects [11]. The MI% observed in these treated epileptics was higher than that obtained by Goyle et al [1].…”

“…It was statistically significant (P < 0.001). This finding as also observed in our previous data [11] suggests that the decrease in PRI is associated with cell cycle delay.…”

“…In vivo and in vitro treatments with various anticonvulsants induce chromosomal aberrations [7] and sister chromatid exchanges [5][6][7][8][9][10][11]. MI and PRI are generally used as cytogenetic end points for the detection of the mutagenic effects of anticonvulsants [1,2, [10][11][12]. Cell cycle kinetics of mutagen-stimulated lymphocytes …”