title: Fluoxetine-induced toxicity results in human placental glutathione S-transferase-π (GST-π) dysfunction.
abstract: BACKGROUND
  The antidepressant drug fluoxetine (FLU) is considered in the group of selective serotonine re-uptake inhibitors. Its distribution in brain and binding to human brain glutathione S-transferase-π (GST-π) have been shown. FLU can cross blood brain barrier and placenta, accumulate in fetus and may cause congenital malformations.
  
  
  OBJECTIVE
  To elucidate the interaction of placental GST-π with FLU.
  
  
  METHODS
  First, concentration-dependent inhibition of human placental GST-π was evaluated by using different FLU concentrations and then 0.3125, 0.625, 1.25, 2.5 and 5 mM FLU concentrations were chosen and tested while keeping GSH concentration constant and 1-chloro-2,4-dinitrobenzene (CDNB) concentration varied and vice versa. The data were evaluated with different kinetic models and Statistica 9.00 for Windows.
  
  
  RESULTS
  The Vm, at variable [CDNB] (142 ± 16 U/mg protein) was 3 times higher than the Vm obtained at variable [GSH] (49 ± 4 U/mg protein). On the other hand, the Km for CDNB was ∼10 times higher than the Km for GSH (1.99 ± 0.36 mM versus 0.21 ± 0.06 mM). The IC50 value for FLU was 8.6 mM. Both at constant [CDNB] and variable [GSH] and at constant [GSH] and variable [CDNB] the inhibition types were competitive with the Ki values of 5.62 ± 4.37 and 8.09 ± 1.27 mM, respectively.
  
  
  CONCLUSIONS
  Although the Ki values obtained for FLU in vitro are high, due to their uneven distribution, long elimination time and inhibitory behavior on detoxification systems, it may cause defects in adults but these effects may be much more severe in fetus and result in congenital malformations.
authors.affiliation: a Department of Medical Biochemistry , Faculty of Medicine, Near East University , Nicosia , Mersin 10 , Turkey and.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Dalmizrak
authors.affiliation: b Department of Medical Biochemistry , Faculty of Medicine, Hacettepe University , Sihhiye , Ankara , Turkey.
authors.forename: Gulnihal
authors.initials: G
authors.lastname: Kulaksiz-Erkmen
authors.affiliation: a Department of Medical Biochemistry , Faculty of Medicine, Near East University , Nicosia , Mersin 10 , Turkey and.
authors.forename: Nazmi
authors.initials: N
authors.lastname: Ozer
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000633:toxicity*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D006801:Humans; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D011247:Pregnancy; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D051549:Glutathione S-Transferase pi; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Human placental GST-π; IC50; competitive inhibition; fluoxetine; kinetics