25 results on '"Seifried HE"'
Search Results
2. BMI Is Associated With Increased Plasma and Urine Appearance of Glucosinolate Metabolites After Consumption of Cooked Broccoli.
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Charron CS, Vinyard BT, Jeffery EH, Ross SA, Seifried HE, and Novotny JA
- Abstract
Introduction: Preclinical studies suggest that brassica vegetable diets decrease cancer risk, but epidemiological studies show varied effects, resulting in uncertainty about any health impact of brassicas. Factors controlling absorption of glucosinolate metabolites may relate to inconsistent results. We reported previously that subjects with BMI > 26 kg/m
2 (HiBMI), given cooked broccoli plus raw daikon radish (as a source of plant myrosinase) daily for 17 days, had lower glucosinolate metabolite absorption than subjects given a single broccoli meal. This difference was not seen in subjects with BMI < 26 kg/m2 (LoBMI). Our objective in this current study was to determine whether a similar response occurred when cooked broccoli was consumed without a source of plant myrosinase. Methods: In a randomized crossover study ( n = 18), subjects consumed no broccoli for 16 days or the same diet with 200 g of cooked broccoli daily for 15 days and 100 g of broccoli on day 16. On day 17, all subjects consumed 200 g of cooked broccoli. Plasma and urine were collected for 24 h and analyzed for glucosinolate metabolites by LC-MS. Results: There was no effect of diet alone or interaction of diet with BMI. However, absorption doubled in HiBMI subjects (AUC 219%, plasma mass of metabolites 202% compared to values for LoBMI subjects) and time to peak plasma metabolite values and 24-h urinary metabolites also increased, to 127 and 177% of LoBMI values, respectively. Conclusion: BMI impacts absorption and metabolism of glucosinolates from cooked broccoli, and this association must be further elucidated for more efficacious dietary recommendations. Clinical Trial Registration: This trial was registered at clinicaltrials.gov (NCT03013465)., (Copyright © 2020 Charron, Vinyard, Jeffery, Ross, Seifried and Novotny.)- Published
- 2020
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3. Broccoli consumption affects the human gastrointestinal microbiota.
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Kaczmarek JL, Liu X, Charron CS, Novotny JA, Jeffery EH, Seifried HE, Ross SA, Miller MJ, Swanson KS, and Holscher HD
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- Adult, Aged, Bacteroidetes, Body Mass Index, Feces microbiology, Female, Humans, Male, Middle Aged, Brassica, Gastrointestinal Microbiome genetics
- Abstract
The human gastrointestinal microbiota is increasingly linked to health outcomes; however, our understanding of how specific foods alter the microbiota is limited. Cruciferous vegetables such as broccoli are a good source of dietary fiber and phytonutrients, including glucosinolates, which can be metabolized by gastrointestinal microbes. This study aimed to determine the impact of broccoli consumption on the gastrointestinal microbiota of healthy adults. A controlled feeding, randomized, crossover study consisting of two 18-day treatment periods separated by a 24-day washout was conducted in healthy adults (n=18). Participants were fed at weight maintenance with the intervention period diet including 200 g of cooked broccoli and 20 g of raw daikon radish per day. Fecal samples were collected at baseline and at the end of each treatment period for microbial analysis. Beta diversity analysis indicated that bacterial communities were impacted by treatment (P=.03). Broccoli consumption decreased the relative abundance of Firmicutes by 9% compared to control (P=.05), increased the relative abundance of Bacteroidetes by 10% compared to control (P=.03) and increased Bacteroides by 8% relative to control (P=.02). Furthermore, the effects were strongest among participants with body mass index <26 kg/m
2 , and within this group, there were associations between bacterial relative abundance and glucosinolate metabolites. Functional prediction revealed that broccoli consumption increased the pathways involved in the functions of the endocrine system (P=.05), transport and catabolism (P=.04), and energy metabolism (P=.01). These results reveal that broccoli consumption affects the composition and function of the human gastrointestinal microbiota., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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4. Comparison of Effects of Diet on Mammary Cancer: Efficacy of Various Preventive Agents and Metabolomic Changes of Different Diets and Agents.
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Lubet RA, Beger RD, Miller MS, Luster J, Seifried HE, and Grubbs CJ
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- Animals, Antineoplastic Agents pharmacokinetics, Female, Mammary Neoplasms, Experimental chemically induced, Mammary Neoplasms, Experimental metabolism, Metabolomics, Methylnitrosourea administration & dosage, Methylnitrosourea toxicity, Rats, Rats, Sprague-Dawley, Time Factors, Treatment Outcome, Antineoplastic Agents administration & dosage, Diet, High-Fat adverse effects, Food-Drug Interactions, Mammary Neoplasms, Experimental drug therapy
- Abstract
To determine the effects of diet, rats were placed on a standard diet (4% fat) or on a modified Western (high-fat diet, HFD) diet (21% fat) at 43 days of age (DOA) and administered methylnitrosourea (MNU) at 50 DOA. Rats were administered effective (tamoxifen, vorozole, and Targretin) or ineffective (metformin and Lipitor) chemopreventive agents either by daily gavage or in the diet beginning at 57 DOA and continuing until sacrifice (190 DOA). Latency period of the tumors was determined by palpation, and multiplicity and cancer weights per rat were determined at final sacrifice. Rats on the HFD versus standard diet had: (i) a 6% increase in final body weights; (ii) significant decreases in tumor latency; and (iii) significant increases in final tumor multiplicity and average tumor weight. Tamoxifen, vorozole, and Targretin were highly effective preventive agents, whereas Lipitor and metformin were ineffective in rats on either diet. Serum was collected at 78 DOA and at sacrifice (190 DOA), and metabolomics were determined to identify the metabolite changes due to diets and effective agents. Rats given the HFD had increased levels of saturated free fatty acids (including myristate) and decreased levels of 2-aminooctanoate. Furthermore, rats on the HFD diet had increased levels of 2-aminobutyrate and decreases in glycine markers previously identified as indicators of prediabetes. Targretin increased long-chain glycophospholipids (e.g., oleyl-linoleoyl-glycerophosphocholine) and decreased primary bile acids (e.g., taurocholate). Tamoxifen increased palmitoyl-linoleoyl-glycophosphocholine and decreased stearoyl-arachidonyl glycophosphocholine. Finally, increased levels of methylated nucleotides (5-methylcytidine) and decreased levels of urea cycle metabolites (N-acetylcitrulline) were associated with the presence of mammary cancers., (©2018 American Association for Cancer Research.)
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- 2018
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5. Absorption and metabolism of isothiocyanates formed from broccoli glucosinolates: effects of BMI and daily consumption in a randomised clinical trial.
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Charron CS, Vinyard BT, Ross SA, Seifried HE, Jeffery EH, and Novotny JA
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- Acetylcysteine chemistry, Adult, Aged, Anticarcinogenic Agents, Area Under Curve, Cooking, Cross-Over Studies, Female, Genotype, Glucose analogs & derivatives, Glucose chemistry, Glutathione Transferase metabolism, Glycoside Hydrolases metabolism, Humans, Imidoesters chemistry, Isothiocyanates blood, Isothiocyanates chemistry, Isothiocyanates urine, Male, Mannitol chemistry, Middle Aged, Oximes, Raphanus, Sulfides blood, Sulfides chemistry, Sulfides urine, Sulfoxides, Tandem Mass Spectrometry, Thiocyanates blood, Thiocyanates chemistry, Thiocyanates urine, Body Mass Index, Brassica chemistry, Diet, Glucosinolates chemistry, Isothiocyanates metabolism
- Abstract
Sulphoraphane originates from glucoraphanin in broccoli and is associated with anti-cancer effects. A preclinical study suggested that daily consumption of broccoli may increase the production of sulphoraphane and sulphoraphane metabolites available for absorption. The objective of this study was to determine whether daily broccoli consumption alters the absorption and metabolism of isothiocyanates derived from broccoli glucosinolates. We conducted a randomised cross-over human study (n 18) balanced for BMI and glutathione S-transferase μ 1 (GSTM1) genotype in which subjects consumed a control diet with no broccoli (NB) for 16 d or the same diet with 200 g of cooked broccoli and 20 g of raw daikon radish daily for 15 d (daily broccoli, DB) and 100 g of broccoli and 10 g of daikon radish on day 16. On day 17, all subjects consumed a meal of 200 g of broccoli and 20 g of daikon radish. Plasma and urine were collected for 24 h and analysed for sulphoraphane and metabolites of sulphoraphane and erucin by triple quadrupole tandem MS. For subjects with BMI >26 kg/m2 (median), plasma AUC and urinary excretion rates of total metabolites were higher on the NB diet than on the DB diet, whereas for subjects with BMI <26 kg/m2, plasma AUC and urinary excretion rates were higher on the DB diet than on the NB diet. Daily consumption of broccoli interacted with BMI but not GSTM1 genotype to affect plasma concentrations and urinary excretion of glucosinolate-derived compounds believed to confer protection against cancer. This trial was registered as NCT02346812.
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- 2018
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6. Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice.
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Tsuji PA, Carlson BA, Anderson CB, Seifried HE, Hatfield DL, and Howard MT
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- Animals, Computational Biology, Dietary Supplements, Gene Expression, Gene Expression Profiling, Inflammation immunology, Interferon-gamma immunology, Interleukin-6 immunology, Mice, RNA, Messenger genetics, RNA, Messenger metabolism, Selenium blood, Selenoproteins genetics, Sequence Analysis, RNA, Sodium Selenite metabolism, Up-Regulation, Interferon-gamma blood, Interleukin-6 blood, Selenium administration & dosage, Selenoproteins metabolism
- Abstract
Selenium is an essential element that is required to support a number of cellular functions and biochemical pathways. The objective of this study was to examine the effects of reduced dietary selenium levels on gene expression to assess changes in expression of non-selenoprotein genes that may contribute to the physiological consequences of selenium deficiency. Mice were fed diets that were either deficient in selenium or supplemented with selenium in the form of sodium selenite for six weeks. Differences in liver mRNA expression and translation were measured using a combination of ribosome profiling, RNA-Seq, microarrays, and qPCR. Expression levels and translation of mRNAs encoding stress-related selenoproteins were shown to be up-regulated by increased selenium status, as were genes involved in inflammation and response to interferon-γ. Changes in serum cytokine levels were measured which confirmed that interferon-γ, as well as IL-6, were increased in selenium adequate mice. Finally, microarray and qPCR analysis of lung tissue demonstrated that the selenium effects on immune function are not limited to liver. These data are consistent with previous reports indicating that adequate selenium levels can support beneficial immune responses, and further identify the IL-6 and interferon-γ pathways as being responsive to dietary selenium intake.
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- 2015
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7. The 15kDa selenoprotein and thioredoxin reductase 1 promote colon cancer by different pathways.
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Tsuji PA, Carlson BA, Yoo MH, Naranjo-Suarez S, Xu XM, He Y, Asaki E, Seifried HE, Reinhold WC, Davis CD, Gladyshev VN, and Hatfield DL
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- Animals, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms enzymology, Colonic Neoplasms metabolism, Gene Expression Profiling, Mice, Mice, Inbred BALB C, Neoplasm Metastasis, Selenoproteins genetics, Thioredoxin Reductase 1 genetics, Colonic Neoplasms pathology, Selenoproteins metabolism, Thioredoxin Reductase 1 metabolism
- Abstract
Selenoproteins mediate much of the cancer-preventive properties of the essential nutrient selenium, but some of these proteins have been shown to also have cancer-promoting effects. We examined the contributions of the 15kDa selenoprotein (Sep15) and thioredoxin reductase 1 (TR1) to cancer development. Targeted down-regulation of either gene inhibited anchorage-dependent and anchorage-independent growth and formation of experimental metastases of mouse colon carcinoma CT26 cells. Surprisingly, combined deficiency of Sep15 and TR1 reversed the anti-cancer effects observed with down-regulation of each single gene. We found that inflammation-related genes regulated by Stat-1, especially interferon-γ-regulated guanylate-binding proteins, were highly elevated in Sep15-deficient, but not in TR1-deficient cells. Interestingly, components of the Wnt/β-catenin signaling pathway were up-regulated in cells lacking both TR1 and Sep15. These results suggest that Sep15 and TR1 participate in interfering regulatory pathways in colon cancer cells. Considering the variable expression levels of Sep15 and TR1 found within the human population, our results provide insights into new roles of selenoproteins in cancer.
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- 2015
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8. Opportunities for small nutrition-related cancer research grants (R03) from the National Cancer Institute.
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Nicastro HL, Seifried HE, and Milner JA
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- Animals, Humans, Nutritional Sciences economics, Peer Review, Research, Research Personnel education, United States, Biomedical Research economics, National Cancer Institute (U.S.), Research Support as Topic
- Abstract
Small research grants, or R03 grants, provide limited, short-term support for individual research projects. R03s may be an excellent means of support for projects by nutrition scientists at all stages in their careers. The National Cancer Institute (NCI) has awarded roughly one-half of all nutrition-related NIH R03 grants in the period from 2005 to 2010. A detailed review of the recent NCI grant portfolio identified potential strategies for successful applications. Projects that addressed important nutrition and cancer issues had feasible and appropriate specific aims, were innovative, and were based on sound concepts were most positively viewed by reviewers. Furthermore, applicants with suitable expertise, training, mentorship, and records of accomplishment who, when appropriate, collaborated with investigators with complementary knowledge and skills were more likely to receive higher priority scores.
- Published
- 2011
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9. Evaluation of commercial kava extracts and kavalactone standards for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.
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Whittaker P, Clarke JJ, San RH, Betz JM, Seifried HE, de Jager LS, and Dunkel VC
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- Animals, Cell Line, Tumor, Chromatography, High Pressure Liquid, Cytotoxins chemistry, Humans, Kava chemistry, Lactones chemistry, Liver metabolism, Liver ultrastructure, Lymphoma genetics, Mass Spectrometry, Mice, Mutagenicity Tests, Mutation drug effects, Mutation genetics, Plant Extracts toxicity, Subcellular Fractions metabolism, Subcellular Fractions ultrastructure, Cytotoxins toxicity, Kava toxicity, Lactones toxicity, Mutagens
- Abstract
Kava (Piper methysticum) is a member of the pepper family and has been cultivated by South Pacific islanders for centuries and used as a social and ceremonial drink. Traditionally, kava extracts are prepared by grinding or chewing the rhizome and mixing with water and coconut milk. The active constituents of kava are a group of approximately 18 compounds collectively referred to as kavalactones or kava pyrones. Kawain, dihydrokawain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are the six major kavalactones. Kava beverages and other preparations are known to be anxiolytic and are used for anxiety disorders. Dietary supplements containing the root of the kava shrub have been implicated in several cases of liver toxicity in humans, including several who required liver transplants after using kava supplements. In order to study the toxicity and mutagenicity, two commercial samples of kava, Kaviar and KavaPure, and the six pure kavalactones including both D-kawain and DL-kawain, were evaluated in L5178Y mouse lymphoma cells. Neither the kava samples nor the kavalactones induced a mutagenic response in the L5178Y mouse lymphoma mutation assay with the addition of human liver S9 activation.
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- 2008
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10. A review of the interaction among dietary antioxidants and reactive oxygen species.
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Seifried HE, Anderson DE, Fisher EI, and Milner JA
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- Animals, Antioxidants administration & dosage, Cardiovascular Diseases drug therapy, Cardiovascular Diseases metabolism, Diet, Humans, Models, Biological, Neoplasms drug therapy, Neoplasms metabolism, Signal Transduction, Antioxidants therapeutic use, Cardiovascular Diseases prevention & control, Neoplasms prevention & control, Reactive Oxygen Species metabolism
- Abstract
During normal cellular activities, various processes inside of cells produce reactive oxygen species (ROS). Some of the most common ROS are hydrogen peroxide (H(2)O(2)), superoxide ion (O(2)(-)), and hydroxide radical (OH(-)). These compounds, when present in a high enough concentration, can damage cellular proteins and lipids or form DNA adducts that may promote carcinogenic activity. The purpose of antioxidants in a physiological setting is to prevent ROS concentrations from reaching a high-enough level within a cell that damage may occur. Cellular antioxidants may be enzymatic (catalase, glutathione peroxidase, superoxide dismutase) or nonenzymatic (glutathione, thiols, some vitamins and metals, or phytochemicals such as isoflavones, polyphenols, and flavanoids). Reactive oxygen species are a potential double-edged sword in disease prevention and promotion. Whereas generation of ROS once was viewed as detrimental to the overall health of the organism, advances in research have shown that ROS play crucial roles in normal physiological processes including response to growth factors, the immune response, and apoptotic elimination of damaged cells. Notwithstanding these beneficial functions, aberrant production or regulation of ROS activity has been demonstrated to contribute to the development of some prevalent diseases and conditions, including cancer and cardiovascular disease (CVD). The topic of antioxidant usage and ROS is currently receiving much attention because of studies linking the use of some antioxidants with increased mortality in primarily higher-risk populations and the lack of strong efficacy data for protection against cancer and heart disease, at least in populations with adequate baseline dietary consumption. In normal physiological processes, antioxidants effect signal transduction and regulation of proliferation and the immune response. Reactive oxygen species have been linked to cancer and CVD, and antioxidants have been considered promising therapy for prevention and treatment of these diseases, especially given the tantalizing links observed between diets high in fruits and vegetables (and presumably antioxidants) and decreased risks for cancer.
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- 2007
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11. Oxidative stress and antioxidants: a link to disease and prevention?
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Seifried HE
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- Animals, Humans, National Institutes of Health (U.S.), Neoplasms prevention & control, Polymorphism, Genetic, United States, Antioxidants therapeutic use, Genes physiology, Neoplasms etiology, Oxidative Stress physiology
- Abstract
The thrust of this presentation takes a more programmatic approach and gives an overview of the programs at the NIH and the NCI that have a broad nutritional and basic science undercurrent and outline. Also discussed briefly are some areas of general concern that are under investigation in the nutrition group and are included in the group's outreach efforts among professional and academic organizations. The overarching focus of these efforts is to stress the importance of nutrition as a potential modulator of health/disease risks associated with genetic predisposition and environmentally induced disease from diet, lifestyle and exposure to pollutants.
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- 2007
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12. A compilation of two decades of mutagenicity test results with the Ames Salmonella typhimurium and L5178Y mouse lymphoma cell mutation assays.
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Seifried HE, Seifried RM, Clarke JJ, Junghans TB, and San RH
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- Animals, Drug-Related Side Effects and Adverse Reactions, Mice, Mutagenicity Tests, Tumor Cells, Cultured drug effects, Data Collection, Leukemia L5178, Mutagens toxicity, Mutation, Salmonella typhimurium drug effects
- Abstract
As previously reported [Cameron, T. P., Rogers-Back, A. M., Lawlor, T. E., Harbell, J. W., Seifried, H. E., and Dunkel, V. C. (1991) Gentoxicity of multifunctional acrylates in the Salmonella/mammalian-microsome assay and mouse lymphoma TK+/- assay. Environ. Mol. Mutagen. 17, 264-271], the National Cancer Institute (NCI) shares the responsibility of selecting the most significant chemicals for carcinogenicity testing by the National Toxicology Program (NTP) and has used data from Salmonella and mouse lymphoma mutagenicity assays to aid in the selection and prioritization of chemicals to be further evaluated in chronic 2 year rodent studies. In addition, a number of antineoplastic and anti-AIDS drugs in preclinical evaluation were tested for the NCI's Division of Cancer Treatment Toxicology Branch. In the NCI/NTP chemical selection process, it is no longer necessary to test chemicals prior to sending them to the NTP so the NCI program has ceased performing mutagenicity tests. Some of the testing data has been made available in summary form in the Chemical Carcinogenisis Research Information System (CCRIS), which is searchable on the NLM TOXNET system. The limitations in using this source are that only summary results are available and many negative test results are not included. A summary table that presents the results for each compound is provided in the Appendix with raw data provided in the Supporting Information. The Appendix table contains the compound name, CAS number, and a summary of the data from the Ames test and the mouse lymphoma assay.
- Published
- 2006
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13. Mutagenicity of chromium picolinate and its components in Salmonella typhimurium and L5178Y mouse lymphoma cells.
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Whittaker P, San RH, Clarke JJ, Seifried HE, and Dunkel VC
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- Animals, Cell Line, Tumor, Cell Survival drug effects, Chromium toxicity, Cricetinae, In Vitro Techniques, Liver drug effects, Liver metabolism, Lymphoma pathology, Mesocricetus, Mice, Mutagenicity Tests, Rats, Rats, Sprague-Dawley, Salmonella typhimurium drug effects, Tumor Stem Cell Assay, Lymphoma genetics, Mutagens, Picolinic Acids toxicity, Salmonella typhimurium genetics
- Abstract
Chromium picolinate is one of the most commonly used chromium dietary supplements available in the United States, and it has been marketed to consumers for use in weight loss, increasing muscle mass, and lowering serum cholesterol. Chromium picolinate is a synthetic compound that provides a bioavailable form of Cr(III) that is absorbed better than dietary chromium. However, there are several reports that it can have adverse effects. In order to study the mechanism of observed cellular toxicity and mutagenicity, chromium picolinate and its component compounds, chromium (III) chloride and picolinic acid, were evaluated in Salmonella typhimurium and L5178Y mouse lymphoma cells. Neither chromium picolinate nor chromium chloride induced a mutagenic response in S. typhimurium. However, in the L5178Y mouse lymphoma mutation assay, chromium picolinate induced mutagenic responses without and with the addition of S9.
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- 2005
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14. Free radicals: the pros and cons of antioxidants. Executive summary report.
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Seifried HE, Anderson DE, Sorkin BC, and Costello RB
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- Aging, Animals, Antineoplastic Agents, Apoptosis, Biomarkers, Camellia sinensis chemistry, Combined Modality Therapy, DNA chemistry, DNA Damage, Diet, Flavonoids, Free Radicals, Genetic Variation, Glutathione, Humans, Iron, Neoplasms prevention & control, Neoplasms therapy, Oxidation-Reduction, Oxidative Stress, Phenols, Plant Leaves chemistry, Plants chemistry, Polyphenols, Radiotherapy, Reactive Oxygen Species, Signal Transduction, Superoxide Dismutase genetics, Tea, Antioxidants administration & dosage, Antioxidants analysis, Antioxidants therapeutic use, Nutritional Physiological Phenomena
- Published
- 2004
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15. The antioxidant conundrum in cancer.
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Seifried HE, McDonald SS, Anderson DE, Greenwald P, and Milner JA
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- Antioxidants administration & dosage, Dietary Supplements adverse effects, Humans, Reactive Oxygen Species adverse effects, Reactive Oxygen Species metabolism, Antioxidants adverse effects, Antioxidants pharmacology, Neoplasms drug therapy, Neoplasms prevention & control
- Abstract
The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. However, any health-related effects of interactions between dietary antioxidants and ROS likely depend on the health status of an individual and may also be influenced by genetic susceptibilities. Clinical studies of antioxidant supplementation and changes in either oxidative status, disease risk, or disease outcome have been carried out in healthy individuals, populations at risk for certain diseases, and patients undergoing disease therapy. The use of antioxidants during cancer therapy is currently a topic of heated debate because of an overall lack of clear research findings. Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.
- Published
- 2003
16. Genotoxicity of iron chelators in L5178Y mouse lymphoma cells.
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Whittaker P, Seifried HE, San RH, Clarke JJ, and Dunkel VC
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- Animals, Deferiprone, Lymphoma drug therapy, Lymphoma genetics, Mice, Mutagenicity Tests methods, Phenanthrolines toxicity, Pyridones toxicity, Razoxane toxicity, Tumor Cells, Cultured, Edetic Acid analogs & derivatives, Iron Chelating Agents toxicity
- Abstract
To further study the mechanism of observed iron mutagenicity and cellular toxicity, a number of different iron chelators were evaluated to select a compound that was not mutagenic and had limited toxicity to mouse lymphoma cells. A series of iron chelators including those used clinically, those under development for clinical applications, and those used in nonclinical applications were evaluated. The mutagenic activity of the iron chelators was assessed in L5178Y mouse lymphoma cells. Eight of the 12 iron chelators that were tested induced mutagenic responses both with and without the addition of S9. Among those chelators used clinically or developed for clinical use, the only compound that did not induce a mutagenic response was the starch deferoxamine conjugate. In contrast, deferoxamine mesylate showed the highest toxicity in this group of chemicals and the concentrations leading to toxicity and mutagenicity between the activated and nonactivated assays were not significantly different. The other three chelators that were not mutagenic were Na2EDTA, phytic acid, and ferrozine.
- Published
- 2001
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17. Genotoxicity of iron compounds in Salmonella typhimurium and L5178Y mouse lymphoma cells.
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Dunkel VC, San RH, Seifried HE, and Whittaker P
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- Animals, Dose-Response Relationship, Drug, Iron-Dextran Complex toxicity, Leukemia L5178 pathology, Mice, Mutagenicity Tests, Rats, Rats, Sprague-Dawley, Tumor Cells, Cultured, Iron toxicity, Leukemia L5178 genetics, Mutagens toxicity, Salmonella typhimurium drug effects, Salmonella typhimurium genetics
- Abstract
The mutagenic activity of elemental and salt forms of iron (Fe), including compounds currently being used in dietary supplements and for food fortification, were evaluated for mutagenicity in Salmonella typhimurium and L5178Y mouse lymphoma cells. Except for the weak response obtained with ferrous fumarate, none of the compounds induced a mutagenic response in Salmonella. In the mouse lymphoma assay, responses were related to the Fe compound and/or reduction of ferric (Fe+3) to ferrous (Fe+2). Responses with the elemental forms of Fe were divergent. Electrolytic Fe with a relatively larger particle size and irregular shape was negative. The smaller-sized carbonyl Fe, which after 4 hr attached to and was taken up by the cells, induced mutagenic responses both with and without S9. With ferric chloride (FeCl3) and ferric phosphate (FePO4), there was an increase in mutant frequency only with S9. With the Fe+2 compounds, ferrous sulfate (FeSO4) and ferrous fumarate (FeC4H2O4), positive responses were observed without S9. The Fe chelate, sodium Fe(III)EDTA was positive in both the presence and absence of S9. The lowest effective doses (LED) for induction of mutagenicity were identified for these compounds and an LED ratio calculated. The LED ratio ranges from 1 for FeSO4 to 30 for carbonyl Fe, which are similar to oral LD50 values obtained in animal studies.
- Published
- 1999
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18. Strategy and planning for chemopreventive drug development: clinical development plans II.
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Kelloff GJ, Crowell JA, Hawk ET, Steele VE, Lubet RA, Boone CW, Covey JM, Doody LA, Omenn GS, Greenwald P, Hong WK, Parkinson DR, Bagheri D, Baxter GT, Blunden M, Doeltz MK, Eisenhauer KM, Johnson K, Knapp GG, Longfellow DG, Malone WF, Nayfield SG, Seifried HE, Swall LM, and Sigman CC
- Subjects
- Animals, Anticarcinogenic Agents pharmacology, Cell Transformation, Neoplastic, Clinical Trials as Topic standards, Humans, Neoplasms, Experimental prevention & control, Anticarcinogenic Agents therapeutic use, Clinical Trials as Topic methods, Drug Screening Assays, Antitumor methods, Neoplasms prevention & control
- Abstract
This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs.
- Published
- 1996
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19. Evaluation of the mutagenicity of an N-nitroso contaminant of the sunscreen Padimate O: N-nitroso-N-methyl-p-aminobenzoic acid, 2-ethylhexyl ester (NPABAO).
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Dunkel VC, San RH, Harbell JW, Seifried HE, and Cameron TP
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- Animals, Cricetinae, Drug Contamination, Lymphoma, Male, Mesocricetus, Mice, Microsomes, Liver metabolism, Mutagenicity Tests, Mutagens pharmacology, Nitrosamines pharmacology, Rats, Rats, Sprague-Dawley, Salmonella typhimurium drug effects, Sunscreening Agents pharmacology, Tumor Cells, Cultured, para-Aminobenzoates, 4-Aminobenzoic Acid analysis, Mutagens analysis, Nitrosamines analysis, Sunscreening Agents analysis
- Abstract
The nitrosamine contaminant, N-nitroso-N-methyl-p-aminobenzoic acid, 2-ethylhexyl ester (NPABAO), of the major sunscreen ingredient Padimate O (4-N,N'-dimethylamino-benzoic acid, 2-ethylhexyl ester) was synthesized and tested for mutagenicity in the Salmonella typhimurium and mouse lymphoma L5178Y TK +/- assays. In contrast to the previously reported positive responses in S. typhimurium tester strains TA100 and TA1535 [Loeppky et al., 1991], there were no increases in the number of revertants with strains TA98, TA100, TA1535, and TA1538 in either the Salmonella plate incorporation [Ames et al., 1975] or preincubation [Yahagi et al., 1977] assays. Additional testing with Salmonella, following the modified preincubation procedure [Rogan, 1990] that gave the initial positive response, was also negative. Data from the mouse lymphoma assays were also uniformly negative. During synthesis of NPABAO, small amounts of 4-N,N'-dimethylamino-3-nitrobenzoic acid, 2-ethylhexyl ester (DMANBAO) can be formed. To determine whether the reported positive mutagenicity response of NPABAO could be the result of trace amounts of DMANBAO in the NPABAO, that compound was also synthesized and tested for mutagenicity with Salmonella. Positive responses were obtained with tester strains TA98 and TA 1538 but not with TA100 and TA1535, indicating that DMANBAO was not responsible for the increase in revertants originally reported.
- Published
- 1992
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20. Genotoxicity of multifunctional acrylates in the Salmonella/mammalian-microsome assay and mouse lymphoma TK+/-assay.
- Author
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Cameron TP, Rogers-Back AM, Lawlor TE, Harbell JW, Seifried HE, and Dunkel VC
- Subjects
- Animals, Cricetinae, Male, Mesocricetus, Mice, Rats, Rats, Inbred Strains, Tumor Cells, Cultured drug effects, Acrylates, Leukemia L5178, Microsomes, Liver drug effects, Mutagenicity Tests, Salmonella typhimurium drug effects
- Abstract
Multifunctional acrylates are being used increasingly as replacements for solvents, and occupational and general population exposure to this structural class is expanding. Four multifunctional acrylates and acrylic acid were tested for mutagenicity in the Salmonella typhimurium and mouse lymphoma L5178Y TK+/-assays. In the Salmonella assay, two of the compounds (trimethylolpropane triacrylate and trimethylolpropane trimethacrylate) showed weakly positive results with a single tester strain (TA1535) in the presence of hamster liver S9; the other three compounds were negative. All five compounds were negative in the Salmonella assay without S9 activation. In the mouse lymphoma assay, two of the compounds (acrylic acid and ethylene glycol diacrylate) were positive in both the presence and the absence of S9, one compound was positive only in the presence of S9 (ethylene glycol dimethacrylate), and one compound was positive only in the absence of S9 (trimethylolpropane triacrylate).
- Published
- 1991
- Full Text
- View/download PDF
21. The mechanism of action of cytochrome P-450. Occurrence of the 'NIH shift' during hydroperoxide-dependent aromatic hydroxylations.
- Author
-
Rahimtula AD, O'Brien PJ, Seifried HE, and Jerina DM
- Subjects
- Acetanilides, Animals, Benzene Derivatives, Cytochromes metabolism, Hydroxylation, Male, Methylcholanthrene pharmacology, Microsomes, Liver drug effects, Peroxides, Phenobarbital pharmacology, Rabbits, Rats, Cytochrome P-450 Enzyme System metabolism, Microsomes, Liver enzymology
- Abstract
The mechanism of liver microsomal aromatic hydroxylation has been investigated by using cumene hydroperoxide as the hydroxylating agent and comparing this reaction with the NADPH-dependent reaction. The conversion of [4-(3)H]acetanilide to 4-hydroxyacetanilide by rat liver microsomes (or purified cytochrome P-450) in the presence of either cumene hydroperoxide or NADPH is attended by comparable 'NIH shifts'. This indicates that hydroxylation in the two systems proceeds via a common intermediate, presumably an arene oxide. The intermediacy of an arene oxide, phenanthrene-9,10-oxide, is established by incubating [3-(3)H]-phenanthrene with rat-liver microsomes and cumene hydroperoxide in the presence of either non-radioactive phenanthrene-9,10-oxide as a 'trap' or in the presence of cyclohexene oxide, an inhibitor of the enzyme epoxide hydrase. Incubation of phenanthrene with cumene hydroperoxide in an 18O-enriched medium has confirmed that the oxygen atom in phenanthrene-9,10-oxide is derived from the hydroperoxide and not from the medium.
- Published
- 1978
- Full Text
- View/download PDF
22. Investigation of microsomal oxygenases of biosynthetic processes. Stearyl-CoA desaturase of adipose tissue and liver.
- Author
-
Seifried HE and Gaylor JL
- Subjects
- Animals, Kinetics, Male, Organ Specificity, Rats, Swine, Adipose Tissue enzymology, Fatty Acid Desaturases metabolism, Microsomes enzymology, Microsomes, Liver enzymology, Stearoyl-CoA Desaturase metabolism
- Abstract
Porcine and rat microsomal stearyl-CoA desaturases require reduced pyridine nucleotide and oxygen, are cyanide sensitive, and are insensitive to carbon monoxide. The Km for stearyl-CoA is somewhat larger for liver than for the adipose desaturases, but, in general, assay conditions are quite similar. Adipose tissue microsomes contain cytochromes b5 and P-450, as well as the NADH- and NADPH-specific cytochrome reductases. Compared to liver, the specific contents and activities of electron carriers are much lower in adipose tissue, and activities of 4-methyl sterol oxidase of cholesterol biosynthesis, as well as the cytochrome P-450-dependent aminopyrene demethylase and benzypyrene hydroxylase, are negligible in adipose tissue microsomes. Furthermore, unlike hepatic desaturase, administration of insulin stimulates the adipose desaturase 3-fold without affecting either the amounts or activities of microsomal oxidation-reduction proteins; the changes in desaturase activities produced either by altering dietary fat or by fasting and/or fasting followed by refeeding are, in general, both more extensive and more permanent in adipose compared to liver microsomes. The effects produced by isotopic hydrogen substitution both in stearyl-CoA and in the medium (2H2O) are similar with microsomes from both tissues. The rate-determining step of desaturase appears to be similar in both tissues. The primary isotope effect, k H/Tr, observed with [9,10-3H2]stearyl-CoA is relatively small, 2.88. Since little, if any, primary isotope effect is associated with methyl sterol oxidase, these two mixed function oxidases of biosynthetic processes also appear to share this property in common.
- Published
- 1976
23. Metabolism of benzo[a]pyrene. Effect of 3-methylcholanthrene pretreatment on metabolism by microsomes from lungs of genetically "responsive" and "nonresponsive" mice.
- Author
-
Seifried HE, Birkett DJ, Levin W, Lu AY, Conney AH, and Jerina DM
- Subjects
- Animals, Epoxide Hydrolases metabolism, Lung drug effects, Lung enzymology, Mice, Mice, Inbred A, Mice, Inbred C57BL, Mice, Inbred DBA, Microsomes drug effects, Microsomes enzymology, Microsomes, Liver metabolism, Oxygenases metabolism, Phenols metabolism, Benzopyrenes metabolism, Lung metabolism, Methylcholanthrene pharmacology, Microsomes metabolism
- Published
- 1977
- Full Text
- View/download PDF
24. Anthracene 1,2-oxide: synthesis and role in the metabolism of anthracene by mammals.
- Author
-
Akhtar MN, Hamilton JG, Boyd DR, Braunstein A, Seifried HE, and Jarina DM
- Subjects
- Animals, Male, Methylcholanthrene pharmacology, Microsomes, Liver drug effects, Phenobarbital pharmacology, Rats, Anthracenes metabolism, Epoxide Hydrolases metabolism, Microsomes, Liver metabolism, Oxides metabolism
- Published
- 1979
25. Assay and isolation of a cyanide-binding protein of rat liver microsomes.
- Author
-
Gaylor JL, Moir NJ, Seifried HE, and Jefcoate CR
- Subjects
- Animals, Bile Acids and Salts pharmacology, Chromatography, DEAE-Cellulose, Coenzyme A, Cytochromes, Microsomes, Liver drug effects, Oxidoreductases, Peptide Hydrolases pharmacology, Protein Binding, Rats, Spectrophotometry, Stearic Acids, Sterols metabolism, Cyanides metabolism, Microsomes, Liver metabolism, Proteins isolation & purification
- Published
- 1970
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