Olanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs and are commonly used for the treatments of schizophrenia and bipolar disorders. However, recent reports indicated that these drugs could exhibit toxic effects on nervous and cardiovascular systems. To our best knowledge, there are scarce data considering the genotoxic damage potentials of OLZ, RPD and QTP on human lymphocyte culture system. Therefore, in this study, the genotoxic potentials of OLZ, RPD and QTP (0–400 mg/L) have been evaluated in human whole blood cultures (WBCs; n = 4). The single cell gel electrophoresis (SCGE) and micronucleus (MN) assays were applied to estimate the DNA damage. The results of the present study indicated that the tested antipsychotic drug did not induce genotoxicity. In fact, the mean values of the total scores of cells showing DNA damage (for SCGE assay) and MN/1000 cell were not found significantly different from the control values (p > 0.05). However, the application of the highest drug concentrations (250 mg/L and above) caused the sterility in lymphocyte cultures. It is concluded that the tested three different atypical antipsychotic drugs can be used safely, but it is necessary to consider the cytotoxic effects that are likely to appear depending on the doses exposed.
Abu-KishkIToledanoMReisA (2004) Neuroleptic malignant syndrome in a child treated with an atypical antipsychotic. Journal of Toxicology. Clinical Toxicology42: 921–925.
2.
Al-chalabiBMThanoonIAJAhmedFAA (2009) Potential effect of olanzapine on total antioxidant status and lipid peroxidation in schizophrenic patients. Neuropsychobiology59: 8–11.
3.
AliyaziciogluRKuralBColakM (2007) Treatment with lithium, alone or in combination with olanzapine, relieves oxidative stress but increases atherogenic lipids in bipolar disorder. Tohoku Journal of Experimental Medicine213: 79–87.
4.
AltinkiliçSNaziroğluMUğuzAC (2010) Fish oil and antipsychotic drug risperidone modulate oxidative stress in PC12 cell membranes through regulation of cytosolic calcium ion release and antioxidant system. Journal of Membrane Biology235: 211–218.
5.
BelhaniDFrassatiDMégardR (2007) Cardiac lesions induced by neuroleptic drugs in the rabbit. Experimental and Toxicologic Pathology57: 207–212.
6.
BrambillaGMattioliFMartelliA (2009) Genotoxic and carcinogenic effects of antipsychotics and antidepressants. Toxicology261: 77–88.
7.
ChoongERudazSKottelatA (2009) Therapeutic drug monitoring of seven psychotropic drugs and four metabolites in human plasma by HPLC-MS. Journal of Pharmaceutical and Biomedical Analysis50: 1000–1008.
8.
DasGPShaikAPJamilK (2006) Cytotoxicity and genotoxicity induced by the pesticide profenofos on cultured human peripheral blood lymphocytes. Drug and Chemical Toxicology29: 313–322.
9.
Dietrich-MuszalskaAOlasBGłowackiR (2009) Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia. Neuropsychobiology59: 1–7.
10.
DongENelsonMGraysonDR (2008) Clozapine and sulpiride but not haloperidol orolanzapine activate brain DNA demethylation. Proceedings of National Academy of Sciences of the United States of America105: 13614–13619.
11.
EvansHJO’RiordanML (1975) Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests. Mutation Research31: 135–148.
12.
FenechM (1993) The cytokinesis-block micronucleus technique: a detailed description of the method and its application to genotoxicity studies in human populations. Mutation Research285: 35–44.
13.
GardnerIZahidNMacCrimmonD (1998) A comparison of the oxidation of clozapine andolanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Molecular Pharmacology6: 991–998.
14.
GerberJECawthonB (2000) Overdose and death with olanzapine: two case reports. American Journal ofForensic Medicine and Pathology2: 249–51.
15.
GerlachMHünnerkopfRRothenhöferS (2007) Therapeutic drug monitoring of quetiapine in adolescents with psychotic disorders. Pharmacopsychiatry40: 72–76.
16.
GeyikogluFTurkezH (2005) Protective effect of sodium selenite on genotoxicity to human whole blood cultures induced by aflatoxin B-1. Brazilian Archives of Biology and Technology48: 905–910.
17.
HeatonPRRansleyRCharltonCJ (2002) Application of single-cell gel electrophoresis (comet) assay for assessing levels of DNA damage in canine and feline leukocytes. Journal of Nutrition132: 1598S–1603S.
18.
KizilianNWilkinsRCReinhardtP (1999) Silver-stained comet assay for detection of apoptosis. Biotechniques27: 926–930.
19.
LokshinPDorfmanPShoshaniD (1999) Olanzapine treatment after clozapine induced agranulocytosis. Human Psychopharmacology: Clinical and Experimental13: 583–584.
20.
LostiaAMMazzariniLPacchiarottiI (2009) Serum levels of risperidone and its metabolite, 9-hydroxyrisperidone: correlation between drug concentration and clinical response. Therapeutic Drug Monitoring31: 475–481.
21.
LuYMengQZhangG (2008) Clozapine induced hepatotoxicity in rat hepatocytes by gel entrapment and monolayer culture. Toxicology In Vitro22: 1754–1760.
22.
MauriMCVolonteriLSColasantiA (2007) Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clinical Pharmacokinetics46: 359–388.
MerrickTCFeloJAJenkinsAJ (2001) Tissue distribution of olanzapine in a postmortem case. American Journal ofForensic Medicine and Pathology22: 270–274.
25.
MerrillDBDecGWGoffDC (2005) Adverse cardiac effects associated with clozapine. Journal of Clinical Psychopharmacology25: 32–41.
26.
MishraACMohantyB (2010) Effects of lactational exposure of olanzapine and risperidone on hematology and lymphoid organs histopathology: a comparative study in mice neonates. European Journal of Pharmacology634: 170–177.
27.
MuenchJHamerAM (2010) Adverse effects of antipsychotic medications. American Family Physician81: 617–622.
28.
NazirizadehYVogelFBaderW (2010) Serum concentrations of paliperidone versus risperidone and clinical effects. European Journal of Clinical Pharmacology66: 797–803.
29.
OdaciEBilenHHacimuftuogluA (2009) Long-term treatments with low- and high dose olanzapine change hepatocyte numbers in rats. A stereological and histopathological study. Archives of Medical Research40: 139–145.
30.
OzcanliTErdoganAOzdemirS (2006) Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity. Progress in Neuropsychopharmacology & Biological Psychiatry30: 1163–1166.
31.
OzturkOGumusluS (2004) Age-related changes of antioxidant enzyme activities, glutathione status and lipid peroxidation in rat erythrocytes after heat stress. Life Sciences275: 1551–1565.
32.
PadurariuMCiobicaADobrinI (2010) Evaluation of antioxidant enzymes activities and lipid peroxidation in schizophrenic patients treated with typical and atypical antipsychotics. Neuroscience Letters479: 317–320.
33.
PerticonePCozziRGustavinoB (1987) Sister chromatid exchanges induced by DNA demethylating agents persist through several cell cycles in mammalian cells. Carcinogenesis8: 1059–1063.
PillaiAParikhVJrTerry. (2007) Longterm antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. Journal of Psychiatric Research41: 372–386.
36.
QingHXuHWeiZ (2003) The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP+-induced apoptosis. European Journal of Neuroscience17: 1563–1570.
37.
Saleha BanuBDana DeviKMahboobM (2000) In vivo genotoxic effect of zinc sulfate in mouse peripheral blood leukocytes using comet assay. Drug and Chemical Toxicology24: 63–73.
38.
SaracinoMAde PalmaABoncompagniG (2010) Analysis of risperidone and its metabolite in plasma and saliva by LC with coulometric detection and a novel MEPS procedure. Talanta81: 1547–1553.
39.
SatoMKitauraKMinamiT (2007) Hypothermia-related testicular toxicity of reserpine in mice. Experimental and Toxicologic Pathology59: 187–195.
40.
SavoyYEAshtonMAMillerMW (2010) Differential effects of various typical and atypical antipsychotics on plasma glucose and insulin levels in the mouse: evidence for the involvement of sympathetic regulation. Schizophrenia Bulletin36: 410–418.
41.
SinghNPMcCoyMTTiceRR (1998) A simple technique for quantitation of low level of DNA damage in individual cells. Experimental Cell Research17: 184–191.
42.
SümegiA (2008) Quetipaine in bipolar disorders. Neuropsychopharmacologia Hungarica10: 281–291.
43.
TanHHHoppeJHeardKA (2009) Systematic review of cardiovascular effects after atypical antipsychotic medication overdose. American Journal of Emergency Medicine27: 607–616.
44.
TiceRRAgurellEAndersonD (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environmental and Molecular Mutagenesis35: 206–221.
45.
TrentonACurrierGZwemerF (2003) Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs17: 307–324.
46.
TurkezH (2011) The role of ascorbic acid on titanium dioxide-induced genetic damage assessed by the comet assay and cytogenetic tests. Experimental and Toxicologic Pathology63: 453–457.
47.
TurkezHTogarB (2010) The genotoxic and oxidative damage potential of olanzapine in vitro. Toxicology and Industrial Health26: 583–588.
48.
VojdaniAGhoneumMChoppaP (1997) Minimizing cancer risk using molecular techniques: a review. Toxicology and Industrial Health13: 589–626.
49.
Walss-BassCWeintraubSTHatchJ (2008) Clozapine causes oxidation of proteins involved in energy metabolism: a possible mechanism for antipsychotic-induced metabolic alterations. International Journal of Neuropsychopharmacology11: 1097–1104.
50.
WangHXuHDyckLE (2005) Olanzapine and quetiapine protect PC12 cells from beta-amyloid peptide (25-35)-induced oxidative stress and the ensuing apoptosis. Journal of Neuroscience Research81: 572–580.
51.
WrightonSARingBJ (1999) Predicting drug interactions and pharmacokinetic variability with in vitro methods: the olanzapine experience. Drug Metabolism Reviews31: 15–28.
52.
WultschGMišíkMNersesyanA (2011) Genotoxic effects of occupational exposure measured in lymphocytes of waste-incinerator workers. Mutation Research720: 3–7.
