Evaluation of Duloxetine as Micronuclei Inducer in an Acute and a Subchronic Assay in Mouse

Abstract

Duloxetine is a widely used antidepressant worldwide. In the present report, we evaluated its capacity to induce micronucleated polychromatic erythrocytes (MNPEs) and micronucleated normochromatic erythrocytes (MNNEs) in mice. Two assays were performed, one with a single chemical administration and the other with daily chemical administration. In the first, we administered the antidepressant once to groups of 5 mice by the intragastric (i.g.) route (2, 20, and 200 mg/kg) and performed the analysis at 24, 48, and 72 h postadministration. A control group administered i.g. distilled water was included in the assay, as well as another treated with the micronuclei-inducing chemical daunorubicin (2.5 mg/kg, injected intraperitoneally (i.p.)). In this assay, we found significant damage induced by duloxetine starting from the first time evaluated, showing the highest MNPE increase at the end of the assay. We observed a saturation effect as well, suggested by a decreasing relative efficiency with respect to each tested dose. In a second assay, we administered the antidepressant i.g. every day for 5 weeks (2, 6, and 12 mg/kg), and micronuclei analysis was performed at the end of each week. In this study, we also found a significant increase in both MNPEs and MNNEs which was clear by the second week of administration. Our results suggest that short-term as well as cumulative damage is produced by duloxetine. Thus, confirmation of the observed genotoxic potential in other models seems advisable, as well as caution when prescribing this antidepressant.

Genotoxic Evaluation of Duloxetine II. The Effect on the Number of Sister Chromatid Exchanges, the Mitotic Index, and the Proliferation Kinetics in Mouse Bone Marrow

“…Furthermore, in mouse bone marrow it was also reported that fluoxetine induced a duplication of SCE in comparison with the control level, no alteration in the cellular proliferation kinetics, and a weak decrease of the mitotic index with the highest tested dose. 25) Our present results demonstrated a genotoxic capacity of duloxetine which corresponded to an increase of about 58% over the control value with the three tested doses, an effect that although lower, agrees with a previous report that examined the drug as a micronuclei inducer, 9) as well as with a study in progress to determine the kinetics of DNA damage with the comet assay in liver and brain cells. The absence of dose response in the present assay could be in line with a strong genotoxic effect of the drug which starts from the first dose; this was shown with the calculation of the total genotoxic efficiency in our previous assay which used the same doses (2, 20, and 200 mg/kg), calculation which also suggested a decrease in the relative efficiency with respect to each of the applied doses, besides a dose-saturation effect.…”

“…Since the drug's approval in the first years of the present century its use has been substantially increased as shown by the account of about 42% of the antidepressant sales in 2012, and a major share of about 11 billion dollar/year. 14,15) However, organic collateral damage has been occasionally reported as well as moderate to severe withdrawal syndrome and the induction of DNA disturbances 9,16,17) ; moreover, the medicament can be used for weeks or months, a characteristic which suggests the pertinence of carrying out further toxicity tests that may be useful for the safety recommendations on its consumption. In this context, SCE has become a useful cytogenetic biomarker after the discovery that incorporation of the DNA base analog BrdU in combination with Höechst dye staining produced clear chromatid differentiation and revealed SCE.…”

“…The absence of dose response in the present assay could be in line with a strong genotoxic effect of the drug which starts from the first dose; this was shown with the calculation of the total genotoxic efficiency in our previous assay which used the same doses (2, 20, and 200 mg/kg), calculation which also suggested a decrease in the relative efficiency with respect to each of the applied doses, besides a dose-saturation effect. 9) Moreover, the obtained results may be related with the oxidative potential of duloxetine, which was suggested by the presence of naphthyl and hydroxyl groups in the structure of the studied compound, and because in a preliminary assay, we determined a significant elevation of liver lipoperoxidation induced with the three doses as early as at 3 h of administration; such an effect was maintained up to 9 h before its decrease, also with a significant elevation of brain lipoperoxidation with the two high doses at 3 h of exposure, and with the three tested doses at 9 h, followed by a decrease in the effect; this was a similar effect determined likewise regarding the oxidized proteins in the two examined tissues. 26) In conclusion, our assay determined a moderate but significant potential of duloxetine to increase the number of SCE, in addition to no effect regarding the mitotic index, and a small decrease in the cell cycle progression.…”

“…6,7) Studies in the genotoxic field have been reported with heterogeneous results, for example, in a revision made by Barambilla et al, 8) earlier studies have reported negative results with the Ames test, and in the evaluation of mouse bone marrow chromosomal aberrations, sister chromatid exchanges (SCE), and in the DNA damage (observed with the comet assay) in Chinese hamster; however the same authors mention the development of hepatic tumors in female mice treated with 140 mg/kg of the drug for 120 d. In a more recent assay, authors reported a significant increase in the number of micronuclei in an acute and a subchronic assay made in mouse. 9) Besides, DNA damage by xenobiotics is known to originate in distinct forms, knowledge that support the pertinence of evaluating the genotoxic potential through different * To whom correspondence should be addressed. e-mail: eduardo.madrigal@lycos.com Fig.…”

Increase of binucleated cells in the oral mucosa: a study on the use of psychotropics by students of a Brazilian institution

“…However, other assays have been performed. Antidepressants such as Duloxetine (a potent inhibitor of serotonin and noradrenaline reuptake), Imipramine and Desipramine (tricyclic antidepressants) have had their genotoxic capacity previously demonstrated in in vivo assays in a mouse [28][29][30] . The clastogenic, mutagenic and cytotoxic effects of trazodone (serotonergic antidepressant) and milnacipran (inhibitor of serotonin and noradrenaline reuptake) were investigated by using chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (MN), and comet assays in cultured human peripheral lymphocytes 31 .…”