The influence of resveratrol on the activity of hepatic CYP450 isoenzymes in rat
| Authors | |
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| Year of publication | 2007 |
| Type | Article in Proceedings |
| Conference | THE ABSTRACT BOOK, VITAMINS 2007 |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Keywords | polyphenols; resveratrol; cytochrome P450; model of isolated perfused rat liver |
| Description | The enzymatic system of cytochrome P 450 (CYP450) is a part of phase I of enzymatic biotransformation. It consists of many isoenzymes characterized by specific substrates and organ sites which are involved for example in hepatic biotransformation of many drugs. Both, the induction and inhibition of specific CYP450 isoenzymes are important in terms of the efficacy or toxicity of drugs that are substrates for this system. Many factors can influence activity of this enzymatic system. Nutrition state, components of diet and exposure to chemical elements belongs to the most important exogenous ones. Resveratrol, a natural occuring polyphenolic compound, is a part of common human diet and has a various protective biological effects. The knowledge of its influence on the activity of CYP450 hepatic isoenzymes is a crucial information for predicting its interactions with other substrates for CYP450 with implementations to toxicology or clinical pharmacology of this substance. Resveratrol was administered to animals dissolved in 30% DMSO/water solution at the dose of 5 mg/kg/day for 10 days. Folowing substances and its metabolites were used as specific markers for determination of CYP450 isoenzymes activity by HPLC methdos: phenacetine (PHEN)/paracetamol (PAR) (1A2), tolbutamide (TOL)/hydroxytolbutamide (HTOL)(2C6). Perfusate samples were withdrawn in the 10th, 30th, 60th, and 120th minute after addition of specific markers. The strong inhibition of CYP2C6 isoenzyme activity by DMSO manifested by zero concentrations of HTOL in perfusion medium in the case of control rats. No HTOL was also found in the resveratrol pretreated rats. The decreasing concentrations of TOL in the perfusate from controls indicates slow metabolization of TOL during the perfusion. Interestingly, concentrations of TOL in the perfusate from livers of resveratrol treated animals were significantly lower in the 30th minute of perfusion and were increasing in the 60th and 120th minute in comparison to the 30th minute. The elevating trend is not characteristic for the concentrations of marker substance and can be explained by the changes in binding capacity for TOL caused by resveratrol. The mechanism of such influence is still unclear. Metabolization of marker substance phenacetine was more extensive in the case of control group animals. This difference was statistically significant only in the 120th minute at the end of the perfusion. This fact corresponds to the results of other authors describing trans-resveratrol as a moderate inhibitor of CYP1A2 or a substrate of this isoenzyme with the same modifying effect caused by competition with marker substances. This results are in opposition to levels of PAR metabolite PHEN. Its levels were elevated faster during perfusion, but this elevation was not statistically significant when compared to the control animals. |
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