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

Abstract

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-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. Materials and 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 V_m, at variable [CDNB] (142 ± 16 U/mg protein) was 3 times higher than the V_m obtained at variable [GSH] (49 ± 4 U/mg protein). On the other hand, the K_m for CDNB was ∼10 times higher than the K_m 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 K_i values of 5.62 ± 4.37 and 8.09 ± 1.27 mM, 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.

• Human placental GST-π
• fluoxetine
• competitive inhibition
• kinetics
• IC₅₀

Declaration of interest

The authors declare that there are no conflict of interests.