Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity

Antyoksydanty a stres środowiskowy, badania spektralne stabilności substancji naturalnych i ich oddziaływanie z molekułą białka

The stability of eight hydroxycinnamic acids (HCAs) during long-term incubation under physiological conditions was studied by UV-VIS absorption spectroscopy and their possibility of binding to a model protein (bovine serum albumin, BSA) under physiological conditions was investigated by tryptophan fluorescence quenching method. The obtained results suggest that the stability of hydroxycinnamic acids is dependent upon its individual structure and duration of incubation. The monosubstituted derivatives (coumaric acids) were stable within the course of long-term incubation, while di- and trisubstituted derivatives decomposed easily. It was found out that all studied compounds changed fluorescence emission spectrum of BSA. The Stern-Volmer analysis was employed in order to explore binding of HCAs to BSA in details. The binding constants (Kb), number of binding sites (n) and the free energy changes (∆G0) were determined. The binding affinity was strongest for rosmarinic acid and ranked in the following order rosmarinic acid > chlorogenic acid > sinapic acid > caffeic acid > ferulic acid > o-coumaric acid > p-coumaric acid > m-coumaric acid. All free energy changes (∆G0) possessed negative sign indicating the spontaneity of HCAs binding to BSA.Badano trwałość ośmiu kwasów hydrooksycynamonowych, HCAs, podczas inkubacji długoterminowej w warunkach fizjologicznych i możliwość ich wiązania się z modelowym białkiem (albuminą, BSA). Uzyskane wyniki pokazały, że trwałość tych kwasów zależy od ich indywidualnej budowy oraz czasu inkubacji. Wyznaczono stałe trwałości (Kb), liczbę miejsc wiązania (n) oraz zmianę wartości energii Gibbsa (∆G0) wiązania HCAs do BSA, który to proces przebiegał samorzutnie