Phytoestrogens (isoflavones and lignans) are receiving increasing attention due to a potential protective effect against a number of complex diseases. However, in order to investigate these associations, it is necessary to accurately quantify the levels of phytoestrogens in foods and biological fluids. We report an assay for three isoflavones (daidzein, genistein, and glycitein), two metabolites of daidzein (O-desmethylangolensin and equol), and two lignans (enterodiol and enterolactone) in human serum using electrospray ionisation liquid chromatography/mass spectrometry (LC/MS) with selective reaction monitoring. A simple, highly automated sample preparation procedure requires only 200 microL of sample and utilises one solid-phase extraction stage. Limits of detection are in the region of 10 pg/mL for all analytes except equol, which had a limit of detection of approximately 100 pg/mL. The method developed is suitable for measuring the concentrations of phytoestrogens in blood samples collected from large epidemiological studies. The results of the analysis of serum samples from 300 men and women living in the UK are reported.
. Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). Biochemical Pharmacology, Elsevier, 2011, 81 (7) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 37A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 may be a mechanism of food-drug interaction via inhibition of renal uptake.
Treatment of 1-(benzylselenenyl)-5-butyl-5-nonanol (10) with oxalyl chloride followed by the sodium salt of N-hydroxypyridine-2-thione afforded the corresponding pyridine-2-thione-N-oxycarbonyl (PTOC) oxalate ester which was not isolated but immediately heated to provide 2,2-dibutylselenane (7). This transformation presumably involves a tertiary alkyl radical that undergoes intramolecular homolytic substitution at selenium with loss of the benzyl radical to provide the selenium-containing ring system (7). A similar protocol, when applied to 1-(2-benzylselenenyl-5-methoxyphenyl)-3-methyl-3-heptanol (18) and 1-(2-benzylselenenyl-5-methoxyphenyl)-3,7,11,15-tetramethyl-3-hexadecanol (19), followed by deprotection, afforded the selenium-containing alpha-tocopherol analogues 4 and 1f, respectively, in moderate yields. To the best of our knowledge, these transformations represent the first examples of tertiary radicals involved in homolytic substitution chemistry at selenium.
Thioredoxin (Trx) expression is increased in several human primary cancers and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Novel organotellurium antioxidants, especially a primitive analog of vitamin E (compound 1d) and compounds 7, 9 and 10--all carrying highly functionalized 4-(dialkylamino)phenyltelluro groups to secure high antioxidative capacity--were found to inhibit TrxR with IC50 values in the low micromolar range. Whereas antioxidant 1d also inhibited the growth of MCF-7 human breast cancer cells in culture at a similar level (IC50 = 1.8 microM), the other TrxR inhibitors were inactive in concentrations below about 10 M.
The biotransformation of isoflavones by gut microbiota and by drug metabolizing enzymes plays a crucial role in the understanding of their potential health-promoting effects. The purpose of our work was to develop a simultaneous, sensitive, and robust automated ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to quantify the soy isoflavones daidzein and genistein, their conjugative metabolites, as well as their major microbial degradation products in order to provide a method for use in large clinical trials or animal studies. An automated, 96-well solid-phase extraction method was used to extract the isoflavone analytes from plasma and urine. Separation of genistein, daidzein, and 19 of its metabolites, including five glucuronides, seven sulfates, and two sulfoglucuronides, as well as five microbial metabolites, was achieved in less than 25 min using a sub-2 μm particle column and a gradient elution with acetonitrile/methanol/water as mobile phases. Analysis was performed under negative ionization electrospray MS via the multiple reaction monitoring (MRM). Validation was performed according to the analytical method validation guidelines of Food and Drug Administration (FDA) and International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) consisting of selectivity, accuracy, precision, linearity, limit of detection, recovery, matrix effect, and robustness. All validated parameters essentially matched the FDA and ICH requirements. The application of this method to a pharmacokinetic study in postmenopausal women showed that isoflavones are extensively metabolized in vivo. A robust automated analytical approach was developed, which allows the handling of large sample sizes but nevertheless provides detailed information on the isoflavone metabolite profile leading to a better understanding and interpretation of clinical and animal studies.
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