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THE EFFECT OF (-)-LINALOOL ON THE METABOLIC ACTIVITY OF LIVER CYP ENZYMES IN RATS

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NOSKOVÁ Kristýna DOVRTĚLOVÁ Gabriela ZENDULKA Ondřej ŘEMÍNEK Roman JUŘICA Jan

Rok publikování 2016
Druh Konferenční abstrakty
Citace
Popis Introduction (-)-Linalool is monoterpenic alcohol which is the major floral scent occurring in families Lamiaceae, Lauraceae and Rutaceae. (-)-Linalool is often used in a traditional medicine to treat anxiety or mild depression, however its effect on drug metabolizing enzymes and the consequent drug-drug interactions has not been studied yet. Aims The aim of this study was to reveal the influence of subchronic systemic treatment with (-)-linalool on the metabolic activity of selected CYP enzymes in rat liver. The second aim was to reveal possible inhibitory effect of (-)-linalool on CYP2C6 in vitro. Methods (-)-Linalool was administered intragastrically to male Wistar albino rats for 13 consecutive days at the doses of 40, 120, and 360 mg/kg/day. The control group was treated with vehicle (5% glucose + 1% Tween 20) in an appropriate volume 1 ml/kg. The rat liver microsomal fraction (RLM) was isolated by differential centrifugation and the total protein and CYP content were assessed. CYP metabolic activities were evaluated as a CYP-specific hydroxylation of testosterone and diclofenac with use of HPLC methods and expressed as pmol/ml/min/mg of total microsomal protein. Inhibitory potency of (-)-linalool on CYP2C6 metabolic activity was evaluated in RLM incubated with diclofenac after 10 minutes of pre-incubation with (-)-linalool. Results and Discussion Neither total protein content nor CYP content in RLM were affected by any of treatment regimes. (-)-Linalool showed dose-dependent effect on the rate of testosterone-7? (CYP2A), 2ß- (CYP2B), 6ß- (CYP3A), and 16ß-hydroxylation (CYP2C11) but only dose 360 mg/kg exhibited statistically significant increase in the rate of 7?-hydroxylation of testosterone. (-)-Linalool exhibited also dose-dependent trend on the rate of 4-hydroxylation of diclofenac (CYP2C6) which did not reach statistical significance at any of treatment regimes. Within 10 nM – 1mM (-)-linalool exhibited weak competitive inhibition of CYP2C6, with IC50 of 293 µM. In this study we have evaluated the influence of subchronic administration of (-)-linalool on the metabolic activity of CYP2A, 2B, 2C11, 3A and 2C6 with use of testosterone and diclofenac as specific probe substrates. The dose 360 mg/kg showed statistically significant increase of metabolic activity of CYP2A. According to elsewhere published studies, the dose of 160 mg/day showed anxiolytic effect in patients. The doses tested by ours were much higher and therefore we assume that possible influence of linalool on drug metabolizing enzymes is not clinically relevant and therefore could be considered as safe anxiolytic/antidepressant adjuvant to conventional treatment in the light of drug-drug interactions.
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