title: Glutathione S-transferase pi as a target for tricyclic antidepressants in human brain.
abstract: GST pi, the main glutathione S-transferase isoform present in the human brain, was isolated from various regions of the brain and the in vitro effect of tricyclic antidepressants on its activity was studied. The results indicated that amitripyline and doxepin--derivatives of dibenzcycloheptadiene, as well as imipramine and clomipramine--derivatives of dibenzazepine, inhibit the activity of GST pi from frontal and parietal cortex, hippocampus and brain stem. All these tricyclics are noncompetitive inhibitors of the enzyme with respect to reduced glutathione and noncompetitive (amitripyline, doxepin) or uncompetitive (imipramine, clomipramine) with respect to the electrophilic substrate. Their inhibitory effect is reversible and it depends on the chemical structure of the tricyclic antidepressants rather than on the brain localization of the enzyme. We conclude that the interaction between GST pi and the drugs may reduce their availability in the brain and thus affect their therapeutic activity. On the other hand, tricyclic antidepressants may decrease the efficiency of the enzymatic barrier formed by GST and increase the exposure of brain to toxic electrophiles. Reactive electrophiles not inactivated by GST may contribute in adverse effects caused by these drugs.
authors.affiliation: Department of Biochemistry, Medical University of Warsaw, Warszawa, Poland. akuzma@amwaw.edu.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Barańczyk-Kuźma
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kuźma
authors.forename: Marzena
authors.initials: M
authors.lastname: Gutowicz
authors.forename: Beata
authors.initials: B
authors.lastname: Kaźmierczak
authors.forename: Jacek
authors.initials: J
authors.lastname: Sawicki
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology*; D002997:Clomipramine / Q000494:pharmacology; D004316:Doxepin / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction
chemical_list: D000929:Antidepressive Agents, Tricyclic; D007527:Isoenzymes; D004316:Doxepin; D000639:Amitriptyline; D051549:Glutathione S-Transferase pi; D002997:Clomipramine; D007099:Imipramine