Intersexual differences in inhibitory influence of trans-resveratrol on activity of cytochrome P450 2D2 in rats.
OBJECTIVE
Differences in the metabolism between males and females have been seen over time. Hormonal regulation of cytochrome P450 activity is understood to be involved. Trans-resveratrol (RES) is an estrogenically active plant polyphenol with many protective biological activities including neuroprotection. The present report studied the influence of sex and RES on variances in rat's cytochrome P450 2D2 hepatic metabolic activity.


METHODS
Isolated perfused rat liver was used for determination of cytochrome P450 2D2 activity. Wistar albino rats of both sexes were treated with RES at the dose of 5 mg/kg/day for 10 days prior to liver isolation. Levels of marker substance dextromethorphan (DEM) and its 2D2 specific metabolite dextrorphan (DEX) were measured during perfusion. The metabolic ratios (DEM/DEX) and the levels of DEM and DEX in perfusate were compared.


RESULTS
In the controls, the activity of CYP2D2 was found to be higher in male rats compared to females. RES produced inhibition of CYP2D2, expressed by significant changes of both DEM and DEX levels in males and significant increase of only DEM levels in females. There were no gender changes in DEX levels in RES treated animals whilst DEM levels were significantly increased during the whole perfusion in females.


CONCLUSIONS
The results confirmed gender differences in the metabolic activity of CYP450 2D2 with a higher rate in male rats. RES acted as an inhibitor, however again with greater impact in males than in females. This metabolic divergence could be a cause for different sensitivity or even toxicity of drugs metabolized by the CYP450 2D2.
Zendulka
Ondrej
O
Department of Pharmacology, Masaryk University, Brno, Czech Republic. zendulka@med.muni.cz
Totusek
Jiri
J
Sulcova
Alexandra
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003915:Dextromethorphan / Q000737:chemistry / Q000378:metabolism; D003917:Dextrorphan / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D012727:Sex Characteristics; D013267:Stilbenes / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013267:Stilbenes; D003917:Dextrorphan; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C119985:Cyp2d2 protein, rat; D000077185:Resveratrol