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


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

MOLECULAR AND CELLULAR BIOCHEMISTRY, vol.355, pp.223-231, 2011 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 355
  • Publication Date: 2011
  • Doi Number: 10.1007/s11010-011-0858-6
  • Title of Journal : MOLECULAR AND CELLULAR BIOCHEMISTRY
  • Page Numbers: pp.223-231

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-pi (GST-pi). TCAs can pass through placenta, accumulate in utero baby, and cause congenital malformations. Thus, the study of the interaction of GST-pi with antidepressants is crucial. In this study, the interaction of GST-pi 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 +/- A 0.04 and 3.60 +/- A 1.67 mM, respectively. The V (m) values were varying according to the fixed substrate; [CDNB] fixed, 53 +/- A 3 and [GSH] fixed 182 +/- A 63 U/mg protein. At variable [GSH] and variable [CDNB], the k (cat) values of 7.0 x 10(6) and 1.42 x 10(7) s(-1) and the k (cat)/K (m) values of 4.38 x 10(10) and 3.94 x 10(9) M-1 s(-1) were obtained, respectively. At fixed [CDNB] and variable [GSH], amitriptyline (K (s) = 0.16 +/- A 0.03 mM; alpha = 2.08; and K (i) = 1.75 +/- A 0.37 mM) and clomipramine (K (s) = 0.24 +/- A 0.05 mM; alpha = 1.57; and K (i) = 3.90 +/- A 2.26 mM) showed linear mixed-type inhibition whereas when the varied substrate is CDNB, amitriptyline (K (i) = 4.90 +/- A 0.68 mM) and clomipramine (K (i) = 3.37 +/- A 0.39 mM) inhibition were noncompetitive. The inhibition of GST-pi 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.