RESUMEN

Glucocorticoids are metabolized by the CYP3A isoform of cytochrome P450 and by 11-ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1). Experimental data suggest that post-traumatic stress disorder (PTSD) is associated with an increase in hepatic 11ß-HSD-1 activity and a concomitant decrease in hepatic CYP3A activity. Trans-resveratrol, a natural polyphenol, has been extensively studied for its antipsychiatric properties. Recently, protective effects of trans-resveratrol were found in relation to PTSD. Treatment of PTSD rats with trans-resveratrol allowed the rats to be divided into two phenotypes. The first phenotype is treatment-sensitive rats (TSR), and the second phenotype is treatment-resistant rats (TRRs). In TSR rats, trans-resveratrol ameliorated anxiety-like behavior and reversed plasma corticosterone concentration abnormalities. In contrast, in TRR rats, trans-resveratrol aggravated anxiety-like behavior and decreased plasma corticosterone concentration. In TSR rats, hepatic 11ß-HSD-1 activity was suppressed, with a concomitant increase in CYP3A activity. In TRR rats, the activities of both enzymes were suppressed. Thus, the resistance of PTSD rats to trans-resveratrol treatment is associated with abnormalities in hepatic metabolism of glucocorticoids. The free energy of binding of resveratrol, cortisol, and corticosterone to the human CYP3A protein was determined using the molecular mechanics Poisson-Boltzmann surface area approach, indicating that resveratrol could affect CYP3A activity.

Asunto(s)

Glucocorticoides , Trastornos por Estrés Postraumático , Ratas , Humanos , Animales , Glucocorticoides/farmacología , Glucocorticoides/metabolismo , Corticosterona , Resveratrol/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Citocromo P-450 CYP3A , 11-beta-Hidroxiesteroide Deshidrogenasas , Hidroxiesteroide Deshidrogenasas/genética , Hidroxiesteroide Deshidrogenasas/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1

RESUMEN

The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) is an NADPH-dependent reductase, responsible for the activation of cortisol by reducing cortisone. Resveratrol (RES), a type of natural polyphenol, is reported to be able to slow the progression of cancer and cardiovascular disease and improve the health of mice on a high-calorie diet. In this article, we applied molecular docking and molecular dynamics simulations to investigate the possibility of binding RES to 11ß-HSD-1. The 11ß-HSD-1:RES complex is stable on the µs time scale, and backbone RMSD-based clustering identified three conformations. Special attention was paid to the interaction pattern between the ligand and the target molecule, revealing hydrogen bonds between the hydroxyl group of RES and Thr124, as well as hydrophobic interactions responsible for the binding. In vivo studies demonstrated the ability of resveratrol at a dose of 40 mg/kg to reduce 11ß-HSD-1 activity in the liver of rats under conditions of experimental post-traumatic stress disorder (PTSD), as well as in non-stressed animals. In both cases, the resveratrol-induced reduction in 11ß-HSD-1 activity was accompanied by an increase in plasma corticosterone levels and a decrease in anxiety levels in the plus maze test.