Fluoxetine-induced toxicity results in human placental glutathione S-transferase- (GST-) dysfunction


DALMIZRAK Ö., KULAKSIZ ERKMEN G. , Ozer N.

DRUG AND CHEMICAL TOXICOLOGY, cilt.39, sa.4, ss.439-444, 2016 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 39 Konu: 4
  • Basım Tarihi: 2016
  • Doi Numarası: 10.3109/01480545.2016.1141422
  • Dergi Adı: DRUG AND CHEMICAL TOXICOLOGY
  • Sayfa Sayıları: ss.439-444

Özet

Context: 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- (GST-) 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- with FLU. Materials and methods: First, concentration-dependent inhibition of human placental GST- was evaluated by using different FLU concentrations and then 0.3125, 0.625, 1.25, 2.5 and 5mM 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 V-m, at variable [CDNB] (142 +/- 16U/mg protein) was 3 times higher than the V-m obtained at variable [GSH] (49 +/- 4U/mg protein). On the other hand, the K-m for CDNB was approximate to 10 times higher than the K-m for GSH (1.99 +/- 0.36mM versus 0.21 +/- 0.06mM). The IC50 value for FLU was 8.6mM. Both at constant [CDNB] and variable [GSH] and at constant [GSH] and variable [CDNB] the inhibition types were competitive with the K-i values of 5.62 +/- 4.37 and 8.09 +/- 1.27mM, respectively. Conclusion: Although the K-i 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.