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The inhibition characteristics of human placental glutathione S-transferase-π by tricyclic antidepressants: amitriptyline and clomipramine

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Abstract

Tricyclic antidepressants (TCAs) are the non-selective amine re-uptake inhibitors, well absorbed from small intestine, cross the blood–brain barrrier, distributed in the brain, and are bound to glutathione S-transferase-π (GST-π). TCAs can pass through placenta, accumulate in utero baby, and cause congenital malformations. Thus, the study of the interaction of GST-π with antidepressants is crucial. In this study, the interaction of GST-π with amitriptyline and clomipramine was investigated. The K m values for glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB) were found to be 0.16 ± 0.04 and 3.60 ± 1.67 mM, respectively. The V m values were varying according to the fixed substrate; [CDNB] fixed, 53 ± 3 and [GSH] fixed 182 ± 63 U/mg protein. At variable [GSH] and variable [CDNB], the k cat values of 7.0 × 106 and 1.42 × 107 s−1 and the k cat/K m values of 4.38 × 1010 and 3.94 × 109 M−1 s−1 were obtained, respectively. At fixed [CDNB] and variable [GSH], amitriptyline (K s = 0.16 ± 0.03 mM; α = 2.08; and K i = 1.75 ± 0.37 mM) and clomipramine (K s = 0.24 ± 0.05 mM; α = 1.57; and K i = 3.90 ± 2.26 mM) showed linear mixed-type inhibition whereas when the varied substrate is CDNB, amitriptyline (K i = 4.90 ± 0.68 mM) and clomipramine (K i = 3.37 ± 0.39 mM) inhibition were noncompetitive. The inhibition of GST-π by TCAs means the destruction of its protective role against toxic electrophiles. The effect of antidepressants on fetus will be much severe, thus, the antidepressant therapy of pregnant women should be done with caution.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Hacettepe University, Sihhiye, 06100, Ankara, Turkey

    Ozlem Dalmizrak, Gulnihal Kulaksiz-Erkmen & Nazmi Ozer

  2. Department of Biochemistry, Faculty of Medicine, Near East University, Nicosia, 922022, Mersin 10, Turkey

    Nazmi Ozer

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  1. Ozlem Dalmizrak
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  2. Gulnihal Kulaksiz-Erkmen
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  3. Nazmi Ozer
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Correspondence to Nazmi Ozer.

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Dalmizrak, O., Kulaksiz-Erkmen, G. & Ozer, N. The inhibition characteristics of human placental glutathione S-transferase-π by tricyclic antidepressants: amitriptyline and clomipramine. Mol Cell Biochem 355, 223–231 (2011). https://doi.org/10.1007/s11010-011-0858-6

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