Koncentracijska odvisnost učinka izbranih nesteroidnih protivnetnih učinkovin in piceatanola na androgenih in glukokortikoidnih receptorjih, izraženih v celični liniji MDA-kb2

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Jezik:	Slovenski jezik
Leto izida:	2015
Tipologija:	2.09 - Magistrsko delo
Organizacija:	UL FFA - Fakulteta za farmacijo
Založnik:	[B. Sladič]
UDK:	615.9+615.357(043.3)
COBISS:	4008561
Št. ogledov:	220
Št. prenosov:	0
Ocena:	0 (0 glasov)
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Sekundarni jezik:	Angleški jezik
Sekundarni naslov:	Concentration dependence of the effect of selected nonsteroidal anti-inflammatory drugs and piceatanol on the androgen and glucocorticoid receptors, expressed in MDA-kb2 cell line
Sekundarni povzetek:	Common usage of nonsteroidal anti-inflammatory drugs (NSAID) has led to many longterm and potentially harmful effects for organisms, including human. Many of these effects remain unclarified, although some researches have already confirmed that some drugs, including NDAID, act as endocrine disruptors. The findings of in vitro and in vivo studies so far show, that NSAID are able to modulate estrogen receptor (ER), progesterone receptor (PR) and the peroxisome proliferator activated receptor gamma (PPARγ). Effects of NSAID on other receptors, e. g. androgen receptor (AR) and glucocorticoid receptor (GR) are less studied. With this purpose, we studied in our thesis the effects of selected NSAID on these two receptors. Along with two typical NSAID representatives, diclofenac (DIC) and its metabolite 4-hydroxydiclofenac (4-HD), we also chose paracetamol (PAR) and natural representative with anti-inflammatory effect, piceatannol (PIC). They all have antiinflammatory effect in common, although it is broadly known as a characteristic of NSAID. Most representatives of group of NSAID inhibit two isoforms of cyclooxygenase (COX), COX-1 and COX-2. Diclofenac in lesser extent also inhibits COX-3. They attribute this inhibition also to PAR. As a model system for determination their effects we used the cell line MDA-kb2, which expresses functional androgen and glucocorticoid receptor with the ability to differ agonistic and antagonistic properties of the selected substance. First, we used cytotoxicity test to confirm that selected substances in firstly chosen concentrations show cell survival rate more than 80 %. For DIC, PAR and PIC first non-cytotoxic concentration was 175 μM and for 4- HD it was 250 μM. The first non-cytotoxic concentrations and lower concentrations were used later on with in vitro assay. This was screening luciferase assay based on the activation of transcription of the gene for luciferase. Activation of transcription or level of luciferase activity was used as indicator of the effect of tested substances on AR or GR. The test results showed that all test substances have significant agonistic effect on AR and GR at certain concentrations. Agents DIC and PAR work as agonists of AR at concentrations 175, 100, 10, 1 and 0.1 μM, substance 4-HD at concentrations 250, 100, 10, 1 and 0.001 μM, substance PIC at 175, 100 and 1 μM. Agonistic effect on GR of DIC and PAR was showed at concentration175 μM, substance 4-HD showed this at 250, 100 and 10 μM, PIC at 175, 100 and 10 μM. All tested substances, except PIC, works also as antagonist of AR, namely DIC at concentrations 175, 10, 1 and 0.01 μM, 4-HD at 250, 100, 10, 1 and 0001 μM, PAR at 10,1, 0.01 and 0.001 μM. Weak anti-glucocorticoid effect was evidenced only for substances DIC at concentrations 175 and 100 μM, along with its metabolite 4-HD at concentrations 250 and 100 μM. On the basis of our experimental results, we can claim that selected substances modulate AR and GR. We must not neglect the fact that tested substances are able to modulate AR and GR at therapeutic concentrations and also at lower concentrations, which were also found in water sources in the environment. Definitely more detailed in vitro and in vivo studies are needed to evaluate exact mechanisms of action and potentially harmful effects of the selected substances on androgen and glucocorticoid system.
Sekundarne ključne besede:	endocrine disruptors diclofenac 4-hydroxydiclofenac paracetamol piceatannol androgen receptor glucocorticoid receptor MDA-kb2 cell line;
Vrsta dela (COBISS):	Magistrsko delo/naloga
Komentar na gradivo:	Univ. Ljubljana, Fak. za farmacijo
Strani:	XIV, 75 f.
ID:	12050963