Toxicity of pyrimidine derivatives under oxidative stress conditions: chemiluminescence-based assays in systems containing erythrocytes, mitochondria or blood plasma.
Participation of mono-, di-, and tricyclic pyrimidine derivatives in free radical processes was investigated with the use of luminol-enhanced chemiluminescence in measurements performed in vitro in systems containing erythrocytes, erythrocyte lysate, erythrocyte membranes, mitochondria, mitoplasts or blood plasma. The free radical processes were induced in the investigated systems by tert -butyl hydroperoxide ( t -BuOOH) or 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). Amongst the examined compounds, only derivatives containing the thiol substituent were found to modify the course of chemiluminescence. Effects of both amplification and inhibition of light emission were observed to depend on the structure of a derivative and on the type of a biological (experimental) system. The light emission-amplifying activity was found to be characteristic of the system containing erythrocytes. The results of the investigations point out that the pyrimidine thio-derivatives prolonged the oxidative stress through some interactions mainly with (oxy)hemoglobin, which was related with specific toxicity against erythrocytes. Model investigations in the proposed experimental systems can serve as a useful tool at early stages of the drug discovery process when compounds involved in the interactions connected with the oxidative stress are being selected. On the other hand, this method allows to study mechanisms of the toxic action of xenobiotics on cells (erythrocytes) and organelles (mitochondria), strongly implicated in the free radical generation, and to examine the role of the extracellular liquid (plasma).
Sajewicz
Waldemar
W
Department of Toxicology, Medical University, Traugutta 57/59, PL 54-417 Wrocław, Poland. sajewicz@tox.am.wroc.pl
D000578:Amidines; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D008163:Luminescent Measurements; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D011743:Pyrimidines / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000578:Amidines; D005609:Free Radicals; D011743:Pyrimidines; D013438:Sulfhydryl Compounds; C046728:2,2'-azobis(2-amidinopropane)