Piwowarski Jakub P, Stanisławska Iwona, Granica Sebastian, Stefańska Joanna, Kiss Anna K
Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy (J.P.P., I.S., S.G., A.K.K.), and Department of Pharmaceutical Microbiology, Centre for Preclinical Research and Technology (CePT) (J.S.), Medical University of Warsaw, Warsaw, Poland; Primary Laboratory of Origin: Medical University of Warsaw, Faculty of Pharmacy
Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy (J.P.P., I.S., S.G., A.K.K.), and Department of Pharmaceutical Microbiology, Centre for Preclinical Research and Technology (CePT) (J.S.), Medical University of Warsaw, Warsaw, Poland; Primary Laboratory of Origin: Medical University of Warsaw, Faculty of Pharmacy.
Drug Metab Dispos. 2017 Jun;45(6):657-665. doi: 10.1124/dmd.117.075200. Epub 2017 Mar 10.
In recent years, many xenobiotics derived from natural products have been shown to undergo extensive metabolism by gut microbiota. Ellagitannins, which are high molecular polyphenols, are metabolized to dibenzo[,]pyran-6-one derivatives-urolithins. These compounds, in contrast with their parental compounds, have good bioavailability and are found in plasma and urine at micromolar concentrations. In vivo studies conducted for ellagitannin-containing natural products indicate their beneficial health effects toward inflammation and cancer, which are associated with the formation of urolithins. However, the great majority of in vitro experiments that have revealed the molecular mechanisms responsible for the observed effects were conducted for urolithin aglycones. These studies are thus incongruent with the results of pharmacokinetic studies that clearly indicate that glucuronide conjugates are the dominant metabolites present in plasma, tissue, and urine. The aim of this study was to isolate and structurally characterize urolithin conjugates from the urine of a volunteer who ingested ellagitannin-rich natural products, and to evaluate the potential role of -glucuronidase-triggered cleavage in urolithin disposition. Glucuronides of urolithin A, iso-urolithin A, and urolithin B were isolated and shown to be cleaved by the -glucuronidases released by neutrophils from azurophilic granules upon -formylmethionine-leucyl-phenylalanine stimulation as well as by standard strains and clinical isolates from patients with urinary tract infections. These results justify the hypothesis that the selective activation of urolithin glucuronides by -glucuronidase, which are present at high concentrations at inflammation and infection sites and in the microenvironments of solid tumors, could locally increase the concentration of bioactive urolithin aglycones.
近年来，许多源自天然产物的外源性物质已被证明会在肠道微生物群的作用下发生广泛代谢。鞣花单宁是一种高分子多酚，可代谢为二苯并[，]吡喃 - 6 - 酮衍生物——尿石素。与它们的母体化合物相比，这些化合物具有良好的生物利用度，并且在血浆和尿液中的浓度为微摩尔级。对含鞣花单宁的天然产物进行的体内研究表明，它们对炎症和癌症具有有益的健康影响，这与尿石素的形成有关。然而，绝大多数揭示所观察到的效应背后分子机制的体外实验是针对尿石素苷元进行的。因此，这些研究与药代动力学研究结果不一致，药代动力学研究清楚地表明，葡萄糖醛酸苷结合物是血浆、组织和尿液中存在的主要代谢产物。本研究的目的是从摄入富含鞣花单宁天然产物的志愿者尿液中分离尿石素结合物并对其进行结构表征，并评估β - 葡萄糖醛酸酶引发的裂解在尿石素处置中的潜在作用。尿石素A、异尿石素A和尿石素B的葡萄糖醛酸苷被分离出来，并被证明可被中性粒细胞在N - 甲酰甲硫氨酰 - 亮氨酰 - 苯丙氨酸刺激下从嗜天青颗粒中释放的β - 葡萄糖醛酸酶以及尿路感染患者的标准菌株和临床分离株裂解。这些结果证明了以下假设的合理性：在炎症和感染部位以及实体瘤微环境中高浓度存在的β - 葡萄糖醛酸酶对尿石素葡萄糖醛酸苷的选择性激活可局部增加生物活性尿石素苷元的浓度。
