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

Ozlem Dalmizrak, Özlem Dalmızrak, Gulnihal Kulaksiz-Erkmen, Nazmi Ozer, Nesrin Kartal Özer
Molecular and cellular biochemistry · 2011 · vol. 355(1-2) , pp. 223–231 · doi:10.1007/s11010-011-0858-6 · PMID:21567209 · W2050579487
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Amitriptyline and clomipramine inhibit human placental glutathione S-transferase-π through mixed-type and noncompetitive mechanisms, potentially destroying its protective role against toxic electrophiles and posing severe effects on the fetus.

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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 barrier, 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 × 10(6) and 1.42 × 10(7) s(-1) and the k (cat)/K (m) values of 4.38 × 10(10) and 3.94 × 10(9 )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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MeSH descriptors

Amitriptyline Antidepressive Agents, Tricyclic Clomipramine Glutathione S-Transferase pi Placenta Amitriptyline Antidepressive Agents, Tricyclic Clomipramine Dinitrochlorobenzene Dinitrochlorobenzene Enzyme Assays Female Glutathione Glutathione Glutathione S-Transferase pi Glutathione S-Transferase pi Glutathione S-Transferase pi Humans Kinetics Placenta

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SciLite annotations

organisms 2
human noordeloos 2009062
chemicals 10
amitriptyline clomipramine amine amitriptyline clomipramine glutathione chlorocyclohexane amitriptyline clomipramine amitriptyline

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