Biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9

Abstract

The biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9 yielded three new products, lecaniside A (1), lecaniside B (2), and lecaniside C (3). The chemical structures of these metabolites were elucidated based on extensive spectral data, including 2D NMR and HRMS. The hydrogenation, dealkylation, glycosylation, and O-methylation reactions of these metabolites were observed in the present study. In the in vitro assays, compound 1 displayed a little PTP1B inhibitory activity.     

The metabolism of flubendazole in human liver and cancer cell lines

Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut‐residing nematodes in humans. In addition, FLU is now considered a promising anti‐cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high‐performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) analysis. Precision‐cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non‐cancerous, non‐metastatic) ones. These results support the promising potential of FLU in anti‐cancer therapy.     

基于化合物稳定性探讨炮制对含环烯醚萜类成分中药药性及功效影响的研究进展

环烯醚萜类化合物是具有丰富生物活性的重要中药成分,其在炮制过程中常常发生分解与转化,可能影响饮片质量、中药药性与药效。为掌握并合理控制含有该类成分中药炮制过程中影响药性与药效的因素,制定科学的炮制工艺,有效利用炮制环节的生物转化,通过本草考证和检索国内外研究文献,基于环烯醚萜化合物的结构、性质以及分布分析,总结影响环烯醚萜类化合物稳定性因素,梳理炮制前后含有环烯醚萜类化合物中药药性与药效的变化,发现当pH值小于3、温度高于45℃、相对湿度高于45%、未灭活的酶存在和药材含水量较高时均会促使环烯醚萜类成分分解、转化,含该类成分的中药炮制后药性由寒转温,作用由清转补,此改变的物质基础与炮制过程中环烯醚萜苷类成分的分解与转化密切相关。因此,在炒制、炙、蒸煮过程中应以临床用药目的为依据合理控制上述影响因素,以达到增效目的,保证中药质量、临床疗效及用药安全。     

Metabolism of Chinese Materia Medica in Gut Microbiota and Its Biological Effects

The drug metabolism in gut microbiota draws increasing attentions. After interacting with the gut bacteria, the biological effects of drugs might be altered, leading to toxicity or detoxification, production of potential bioactivities, regulating intestinal absorption, etc. In this review, we will focus on the metabolism of Chinese materia medica(CMM) in mammal gut microbiota and its biological effects to learn the interaction between gut bacteria and drugs through oral route in CMM.     

Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment

Many various xenobiotics permanently enter plants and represent potential danger for their organism. For that reason, plants have evolved extremely sophisticated detoxification systems including a battery of xenobiotic-metabolizing enzymes. Some of them are similar to those in humans and animals, but there are several plant-specific ones. This review briefly introduces xenobiotic-metabolizing enzymes in plants and summarizes present information about their action toward veterinary drugs. Veterinary drugs are used worldwide to treat diseases and protect animal health. However, veterinary drugs are also unwantedly introduced into environment mostly via animal excrements, they persist in the environment for a long time and may impact on the non-target organisms. Plants are able to uptake, transform the veterinary drugs to non- or less-toxic compounds and store them in the vacuoles and cell walls. This ability may protect not only plant themselves but also other organisms, predominantly invertebrates and wild herbivores. The aim of this review is to emphasize the importance of plants in detoxification of veterinary drugs in the environment. The results of studies, which dealt with transport and biotransformation of veterinary drugs in plants, are summarized and evaluated. In conclusion, the risks and consequences of veterinary drugs in the environment and the possibilities of phytoremediation technologies are considered and future perspectives are outlined.     

Applications of mass spectrometry in drug metabolism: 50 years of progress

Abstract

Mass spectrometry plays a pivotal role in drug metabolism studies, which are an integral part of drug discovery and development nowadays. Metabolite identification has become critical to understanding the metabolic fate of drug candidates and to aid lead optimization with improved metabolic stability, toxicology and efficacy profiles. Ever since the introduction of atmospheric ionization techniques in the early 1990s, liquid chromatography coupled with mass spectrometry (LC/MS) has secured a central role as the predominant analytical platform for metabolite identification as LC and MS technologies continually advanced. In this review, we discuss the evolution of both MS technology and its applications over the past 50 years to meet the increasing demand of drug metabolism studies. These advances include ionization sources, mass analyzers, a wide range of MS acquisition strategies and data mining tools that have substantially accelerated the metabolite identification process and changed the overall drug metabolism landscape. Exemplary applications for characterization and identification of both small-molecule xenobiotics and biological macromolecules are described. In addition, this review discusses novel MS technologies and applications, including xenobiotic metabolomics that hold additional promise for advancing drug metabolism research, and offers thoughts on remaining challenges in studying the metabolism and disposition of drugs and other xenobiotics.     

Arzneimittelwechselwirkungen mit Antiepileptika

Drug interactions with antiepileptic agents are based in large part on pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes of the cytochrome P450 (CYP) system, which is of central importance for metabolic elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not only their own plasma levels and efficacy but also that of other antiepileptics and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an increase in plasma concentrations and toxicity of antiepileptics and other drugs. Antiepileptics that are not involved in drug interactions include gabapentin, levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of antiepileptics from the brain. This transport mechanism is inhibited by carbamazepine, which may explain the enhanced clinical efficacy of a combination of carbamazepin with other antiepileptics. Other possible pharmacokinetic interactions are precipitation of antiepileptics in the stomach by antacids or sucralfate and displacement from plasmaprotein binding of one antiepileptic agent by another. Therapeutic drug monitoring (TDM) may be helpful in assessing pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be responsible for the enhanced efficacy of antiepileptic combination therapy. In prescribing drugs, their spectrum of interactions has to be known.     

解读2012年度广西自然科学基金药学类项目指南

本文对2012年度广西自然科学基金药学类项目指南作简要评述，从项目分类和发展方向、创新点、资助范围等方面作深入分析，并提出作者观点，以期为广大药学科技工作者提供帮助，使广西自然科学基金为药学基础和应用基础研究提供更有力的科技支撑。     

Inhibition of Staphylococcus Aureus Mediated by Extracts from Iranian Plants

In order to find new antibacterial agents effective against Staphylococcus aureus, ethanolic extracts of 10 plants were tested. S. aureus (489 samples) were isolated either from healthy carriers (nose and throat) or clinical samples. Out of 489 isolates tested, 98.6% were sensitive to trimethoprim-sulfamethoxazole which was used as the reference antibiotic. From the plant extracts screened for antibacterial activity, Myrtus communis L. (leaves) had the greatest activity, inhibiting the growth of 99% of the isolates. Glycyrrhiza glabra L., Eucalyptus globolus Labill and Menta viridis L., were also active against the isolates inhibiting the growth of 90, 59.5 and 48.7% of the isolates, respectively. All of these extracts were active against the reference strains of S. aureus tested. Saturia hortensis L., Teucrium polium L., and Achillea santolina L., had very little antibacterial activity, while Trigonella foenum graecum L., Echium amoenum Fisch & Mey (flowers) and Juglans regia L. (leaves), had no antibacterial activity against the bacterial isolates.     

Do Interactions Between Gut Ecology and Environmental Chemicals Contribute to Obesity and Diabetes?

Background: Gut microbiota are important factors in obesity and diabetes, yet little is known about their role in the toxicodynamics of environmental chemicals, including those recently found to be obesogenic and diabetogenic.Objectives: We integrated evidence that independently links gut ecology and environmental chemicals to obesity and diabetes, providing a framework for suggesting how these environmental factors may interact with these diseases, and identified future research needs.Methods: We examined studies with germ-free or antibiotic-treated laboratory animals, and human studies that evaluated how dietary influences and microbial changes affected obesity and diabetes. Strengths and weaknesses of studies evaluating how environmental chemical exposures may affect obesity and diabetes were summarized, and research gaps on how gut ecology may affect the disposition of environmental chemicals were identified.Results: Mounting evidence indicates that gut microbiota composition affects obesity and diabetes, as does exposure to environmental chemicals. The toxicology and pharmacology literature also suggests that interindividual variations in gut microbiota may affect chemical metabolism via direct activation of chemicals, depletion of metabolites needed for biotransformation, alteration of host biotransformation enzyme activities, changes in enterohepatic circulation, altered bioavailability of environmental chemicals and/or antioxidants from food, and alterations in gut motility and barrier function.Conclusions: Variations in gut microbiota are likely to affect human toxicodynamics and increase individual exposure to obesogenic and diabetogenic chemicals. Combating the global obesity and diabetes epidemics requires a multifaceted approach that should include greater emphasis on understanding and controlling the impact of interindividual gut microbe variability on the disposition of environmental chemicals in humans.