The effect of the binding of antipsychotics clozapine, ziprasidone and sertindole on the content and reactivity of the thiol group Cys34 of human serum-albumin

[T. Zmijanjac]

133 str.

Hemija - Biohemija / Chemistry - Biochemistry

Pronalaženje veze izmeĎu simptoma shizofrenije i biomarkera oksidativnog stresa moglo bi voditi individualizaciji tretmana ove mentalne bolesti. Dokazano je da je oksidativni stres uključen u nastanak i razvoj shizofrenije i da antipsihotici imaju različite efekte na modulaciju nivoa oksidativnog stresa, odnosno, da različite vrste antipsihotika pokazuju različite efekte na ćelijske antioksidanse ili prooksidanse. U ovoj doktorskoj disertaciјi je ispitano vezivanje atipičnih antipsihotika klozapina, sertindola i ziprazidona za humani serum-albumin (HSA) metodom fluorescentne spektroskopije. Mehanizam gašenja fluorescencije, konstante vezivanja (Ka), broj vezujućih mesta (n) i identifikacija vezujućeg mesta sertindola za HSA, odreĎeni su titracijom rastvora HSA fiksne koncentracije različitim koncentracijama liganda uz merenje intenziteta fluorescencije. Uticaj promene u strukturi HSA nakon vezivanja antipsihotika na njegovu antioksidativnu ulogu ispitan je odreĎivanjem sadržaja i reaktivnosti HSA-SH grupe in vitro (merenjem konstante brzine pseudo prvog reda za reakciju HSA-SH grupe sa 5,5′-ditiobis-(2-nitrobenzoinskom kiselinom)) i in vivo (nakon izolovanja albumina iz seruma pacova). Rezultati su upotpunjeni ispitivanjem efekata izlaganja HSA molekula različitim koncentracijama glukoze na sadržaj krajnjih produkata glikacije, na promenu strukture molekula HSA tokom glikacije, kao i ispitivanjem uticaja simultanog vezivanja masnih kiselina, antipsihotika i glukoze na transportnu i antioksidativnu ulogu HSA. Dobijeni rezultati omogućuju bolje sagledavanje i razumevanje mehanizma vezivanja antipsihotika, odnosno farmakodinamike ovih supstanci, ukazujući da ziprazidon, za razliku od klozapina i sertindola, modulira sadržaj i reaktivnost HSA-SH grupe prema povećanom antioksidativnom (odbrambenom) kapacitetu u cirkulaciji, što može doprineti bezbednijem i efikasnijem tretmanu shizofrenije lekovima iz ove grupe psihofarmaka.

Finding a link between the symptoms of schizophrenia and biomarkers of oxidative stress could lead to the individualization of the treatment of this mental illness. It has been proven that oxidative stress is involved in the onset and development of schizophrenia and that antipsychotics have different effects on modulating the level of oxidative stress. Various types of antipsychotics also show different effects on cellular antioxidants or prooxidants. In this doctoral dissertation, the binding of the atypical antipsychotics clozapine, sertindole, and ziprasidone to human serum albumin (HSA) was examined using fluorescence spectroscopy. The fluorescence quenching mechanism, binding constants (Ka), number of binding sites (n), and identification of the binding site of sertindole for HSA were determined by titrating a fixed concentration of HSA solution with different concentrations of the ligand while measuring the fluorescence intensity. The influence of changes in the structure of HSA after the binding of antipsychotics on its antioxidant role was examined by determining the content and reactivity of the HSA-SH group in vitro (by measuring the pseudo-first-order rate constant for the reaction of the HSA-SH group with 5,5′-dithiobis-(2-nitrobenzoic acid)) and in vivo (after isolating albumin from the serum of rats). The results were completed by examining the effects of exposure of HSA molecules to different concentrations of glucose on the content of glycation end products, on the change in the structure of HSA molecules during glycation, as well as by examining the effect of simultaneous binding of fatty acids, antipsychotics, and glucose on the transport and antioxidant role of HSA. The obtained results enable a better overview and understanding of the binding mechanism of antipsychotics, i.e., the pharmacodynamics of these substances, indicating that ziprasidone, unlike clozapine and sertindole, modulates the content and reactivity of the HSA-SH group according to increased antioxidant (defense) capacity in the circulation, which can contribute to safer and more efficient treatment of schizophrenia with drugs from this group of psychopharmaceuticals.

Humani serum-albumin; klozapin; ziprazidon; sertindol; sadržaj i reaktivnost tiolnih grupa; masne kiseline; glukoza; glikacija; antioksidativna uloga

human serum albumin; clozapine; ziprasidone; sertindole; thiol group content and reactivity; fatty acids; glucose; glycation; antioxidant role

547:577.112.82(043.3)

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