2006
The influence of gender on metabolic activity of enzymatic system of cytochrome P450 in the model of isolated perfused rat liver.
ZAHRADNÍKOVÁ, Lucia, Jan JUŘICA, Ondřej ZENDULKA a Eva HADAŠOVÁZákladní údaje
Originální název
The influence of gender on metabolic activity of enzymatic system of cytochrome P450 in the model of isolated perfused rat liver.
Název česky
Vliv pohlaví na metabolickou aktivitu enzymatickeho systmemu cytochromu P450 na modele izolovaných perfunodvaných jater.
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Vydání
Hradec Králové, New Frontiers in the Research of PhD students, od s. 91-94, 4 s. 2006
Nakladatel
Astraprint, Hradec Králové
Další údaje
Jazyk
angličtina
Typ výsledku
Stať ve sborníku
Obor
30104 Pharmacology and pharmacy
Stát vydavatele
Česká republika
Utajení
není předmětem státního či obchodního tajemství
Organizační jednotka
Lékařská fakulta
ISBN
80-229-8103-X
Klíčová slova anglicky
cytochrome P450; gender; isolated perfused liver
Štítky
Příznaky
Mezinárodní význam, Recenzováno
Změněno: 12. 1. 2009 15:28, doc. PharmDr. Ondřej Zendulka, Ph.D.
V originále
Interindividual variability of activity of oxidative and conjugating enzymes, especially the system of cytochrome P450, can be based on many different factors i.e. gender, age, genetic factors or interactions between simultaneously applied drugs. Such a variability may result in a different pharmacoterapeutical effectivity, adverse effects or toxicity of apllied drug. A suitable model for investigations on the activity of hepatic CYPs 450 and biotransformation processes is represented by the isolated perfused liver. The main advantage of this model, in comparison with other methods used for measuring the CYP activity, are conditions resembling physiological situation in the organism. High correlations between results obtained on the model of isolated perfused liver and results from the whole organism were confirmed by many comparative studies. The histologic microstructure is intact as well as the system of biochemical and physiological mechanisms. On the basis of previous studies we can declare a high level of homology between rat and human subfamilies of CYP 450 1A and 2E. Such similarity is also present in subfamilies 2D and 3A (Guengerich, 1997). CYP enzymes comprise a large family of hemoprotein, and enzymes from three subfamilies (CYP 2C, CYP 2D and CYP 3A) are mainly involved in biotransformation of xenobiotics in both human and rats. Cytochrome P-450 from rats was one of the first isolated and characterized. We studied the influence of gender on selected isoenzymes using the following drugs as specific markers: tolbutamide for CYP 2C6, dextromethorphan for CYP 2D2 and midazolam for CYP 3A2 (Kobayashi et al., 2002, Dostalek et al. 2003). CYP2D2 activity in rat females was significantly higher than in males. Also the final concentration of a marker metabolite (dextrorphan) in females was higher only in CYP2D2. The elevation was 10% in the 60th min and 9% in the 120th min. In contrast activity in CYP subfamily in females was lower than in males. All last three isoforms of CYP450, CYP2C6 (tolbutamid) and CYP1A2 (phenacetin), showed lower activity when compared to CYP2D2, and female metabolization rate was slower than in males. As we expected, the activity of CYP subfamilies differed due to gender. CYP 2D2 activity in rat females was significantly higher than in males (Fig. 1). Also the final concentration of a marker metabolite (dextrorphan) in females was higher only in CYP 2D2. The elevation was 5,7% in the 30th min, 33% in the 60th min and 34% in the 120th min. In contrast activity in CYP 3A subfamily in females was lower than in males. Next two isoforms of CYP450, used as markers were tolbutamid (CYP2C6 – metabolite 4-hydroxytolbutamid) and phenacetin (CYP1A2 – metabolite paracetamol). They showed dramatically lower activity when compared to CYP 2D2, and female metabolization was slower than in males. Thus, the obtained results suggest that the activity of CYP 450 is gender dependent and different dosing schemes for males and females should be used when administering drugs metabolized by CYP 450.
Česky
Preklinické experimenty sú založené na využívaní zvieracích modelov k predikcii vplyvu látky na ľudský oragnizmus. Cytochróm P-450 (CYP-450) hraje kľúčovú úlohu v biotransformačných procesoch veľkého množstva xenobiotík.Interindividuálna variabilita aktivity oxidatívnych a konjugačných enzýmov, hlavne CYP-450, môže byť zapríčinené roznymi faktormi ako napr. druh, pohlavie, vek, genetický základ jedinca, alebo interakcie medzi súčastne podávanými loiečivami, dosledkom čoho može byť rozna farmakoterapeutická účinnosť liečiva , ako aj výskyt a intenzita nežiadúcich až toxických účinkov. Naša pozornosť bola venovaná vplyvu pohlavia na aktivitu izoenzýmov CYP2D2, 1A2 a 2C6, vzhľadom na skutočnosť, že vo vedeckej literatúre je tento faktor variability metabolickej aktivity často vynechaný, alebo sa autori v názoroch rozchádzajú. Na základe nami získaných výsledkov môžeme tvrdiť, že aktivita metabolických izoenzýmov bola len v jednom prípade vyššia u samíc (metabolizovali touto cestou rýchlejšie) než u samcov. Týkalo sa to izoformy CYP2D2, kde bol ako selektívny marker použitý dextrometorfan. Pri ostatných dvoch nami sledovaných izoformách (CYP2C6 – selektívny marker tolbutamid a CYP1A2 – selektívny marker fenacetín) prejavili potkani kmeňa Wistar oproti izoforme 2D2 vyššiu aktivitu, pričom však samice metabolizovali pomalšie ako samci u oboch nami sledovaných typov enzýmu.
Návaznosti
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