Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Oral intake of added titanium dioxide and its nanofraction from food products, food supplements and toothpaste by the Dutch population
    Rompelberg, Cathy ; Heringa, Minne B. ; Donkersgoed, Gerda van; Drijvers, José ; Roos, Agnes ; Westenbrink, Susanne ; Peters, R.J.B. ; Bemmel, M.E.M. van; Brand, Walter ; Oomen, Agnes G. - \ 2016
    National Institute for Public Health and the Environment
    food supplements - foodproducts - TiO 2 intake - Dutch population - Titanium dioxide - TiO 2 NPs - TiO 2 NPs ranges - bw - TiO 2 - TiO 2 ranges
    Titanium dioxide (TiO2) is commonly applied to enhance the white colour and brightness of food products. TiO2 is also used as white pigment in other products such as toothpaste. A small fraction of the pigment is known to be present as nanoparticles (NPs). Recent studies with TiO2 NPs indicate that these particles can have toxic effects. In this paper, we aimed to estimate the oral intake of TiO2 and its NPs from food, food supplements and toothpaste in the Dutch population aged 2 to over 70 years by combining data on food consumption and supplement intake with concentrations of Ti and TiO2 NPs in food products and supplements. For children aged 2–6 years, additional intake via ingestion of toothpaste was estimated. The mean long-term intake to TiO2 ranges from 0.06 mg/kg bw/day in elderly (70+), 0.17 mg/kg bw/day for 7–69-year-old people, to 0.67 mg/kg bw/day in children (2–6 year old). The estimated mean intake of TiO2 NPs ranges from 0.19 μg/kg bw/day in elderly, 0.55 μg/kg bw/day for 7–69-year-old people, to 2.16 μg/kg bw/day in young children. Ninety-fifth percentile (P95) values are 0.74, 1.61 and 4.16 μg/kg bw/day, respectively. The products contributing most to the TiO2 intake are toothpaste (in young children only), candy, coffee creamer, fine bakery wares and sauces. In a separate publication, the results are used to evaluate whether the presence of TiO2 NPs in these products can pose a human health risk.
    Oral intake of added titanium dioxide and its nanofraction from food products, food supplements and toothpaste by the Dutch population
    Rompelberg, Cathy ; Heringa, Minne B. ; Donkersgoed, Gerda van; Drijvers, José ; Roos, Agnes ; Westenbrink, Susanne ; Peters, Ruud ; Bemmel, Greet van; Brand, Walter ; Oomen, Agnes G. - \ 2016
    Nanotoxicology 10 (2016)10. - ISSN 1743-5390 - p. 1404 - 1414.
    Food additive E 171 - long-term dietary intake - nanomaterial - probabilistic modelling - TiO

    Titanium dioxide (TiO2) is commonly applied to enhance the white colour and brightness of food products. TiO2 is also used as white pigment in other products such as toothpaste. A small fraction of the pigment is known to be present as nanoparticles (NPs). Recent studies with TiO2 NPs indicate that these particles can have toxic effects. In this paper, we aimed to estimate the oral intake of TiO2 and its NPs from food, food supplements and toothpaste in the Dutch population aged 2 to over 70 years by combining data on food consumption and supplement intake with concentrations of Ti and TiO2 NPs in food products and supplements. For children aged 2–6 years, additional intake via ingestion of toothpaste was estimated. The mean long-term intake to TiO2 ranges from 0.06 mg/kg bw/day in elderly (70+), 0.17 mg/kg bw/day for 7–69-year-old people, to 0.67 mg/kg bw/day in children (2–6 year old). The estimated mean intake of TiO2 NPs ranges from 0.19 μg/kg bw/day in elderly, 0.55 μg/kg bw/day for 7–69-year-old people, to 2.16 μg/kg bw/day in young children. Ninety-fifth percentile (P95) values are 0.74, 1.61 and 4.16 μg/kg bw/day, respectively. The products contributing most to the TiO2 intake are toothpaste (in young children only), candy, coffee creamer, fine bakery wares and sauces. In a separate publication, the results are used to evaluate whether the presence of TiO2 NPs in these products can pose a human health risk.

    Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction
    Eussen, S.R.B.M. ; Geleijnse, J.M. ; Giltay, E.J. ; Rompelberg, C.J.M. ; Klungel, O.H. ; Kromhout, D. - \ 2012
    European Heart Journal 33 (2012)13. - ISSN 0195-668X - p. 1582 - 1588.
    coronary-heart-disease - placebo-controlled trial - alpha-linolenic acid - omega-3-fatty-acids - cholesterol - metaanalysis - therapy - fish - adults - omega
    Aims Recent secondary prevention trials have failed to demonstrate a beneficial effect of n-3 fatty acids on cardiovascular outcomes, which may be due to the growing use of statins since the mid-1990s. The aim of the present study was to assess whether statins modify the effects of n-3 fatty acids on major adverse cardiovascular events in patients with a history of myocardial infarction (MI). Methods and results Patients who participated in the Alpha Omega Trial were divided into consistent statin users (n = 3740) and consistent statin non-users (n = 413). In these two groups of patients, the effects of an additional daily amount of 400 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), 2 g a-linolenic acid (ALA), or both on major cardiovascular events were evaluated. Multivariable Cox's proportional hazard models were used to calculate adjusted hazard rate ratios (HRadj). Among the statin users 495 (13%) and among the statin non-users 62 (15%) developed a major cardiovascular event. In statin users, an additional amount of n-3 fatty acids did not reduce cardiovascular events [HRadj 1.02; 95% confidence interval (CI): 0.80, 1.31; P = 0.88]. In statin non-users, however, only 9% of those who received EPA–DHA plus ALA experienced an event compared with 18% in the placebo group (HRadj 0.46; 95% CI: 0.21, 1.01; P= 0.051). Conclusion In patients with a history of MI who are not treated with statins, low-dose supplementation with n-3 fatty acids may reduce major cardiovascular events. This study suggests that statin treatment modifies the effects of n-3 fatty acids on the incidence of major cardiovascular events.
    Mogelijkheden voor reductie van medicijngebruik door gezonde voeding(sproducten) in zorginstellingen
    Sluis, A.A. van der; Peppelenbos, H.W. ; Witkamp, R.F. ; Rompelberg, C.J.M. ; Jong, N. de; Verhagen, H. - \ 2009
    Wageningen : AFSG - 29
    verpleeghuizen - geneesmiddelen - voedingsstof-geneesmiddel interacties - voeding en gezondheid - gezondheidszorginstellingen - ouderen - voedingstoestand - nursing homes - drugs - nutrient drug interactions - nutrition and health - health maintenance organizations - elderly - nutritional state
    De nadruk van dit rapport ligt op de volgende twee vragen: 1) In hoeverre kan voeding het gebruik van geneesmiddelen in het algemeen in verpleeghuizen beïnvloeden? Hierbij valt onderscheid te maken in: a) Wat is de rol van omgevingsinvloeden (sociale context)? b) Voedingsproducten: welke specifieke producten kunnen medicijngebruik verminderen? 2) Wat is de kostenefficiëntie van de vervanging van medicijnen door gezonde voedingsproducten? In hoeverre betekent investeren in voeding een besparing op medicijnen of verpleging?
    Foliumzuurverrijking: zowel preventie als bevordering van kanker
    Kloosterman, J. ; Jong, N. ; Rompelberg, C.J.M. ; Kampman, E. ; Ocké, M.C. - \ 2006
    Nederlands Tijdschrift voor Geneeskunde 150 (2006)126. - ISSN 0028-2162 - p. 1443 - 1448.
    foliumzuur - vitamine b complex - foliumzuurtekort - gezondheid - voedseladditieven - voedselverrijking - ziektepreventie - folic acid - vitamin b complex - folic acid deficiency - health - food additives - food enrichment - disease prevention
    In many countries foods are fortified with folic acid to prevent neuraltube defects. Beneficial effects on cancer, cardiovascular diseases and dementia are also assumed. As well as beneficial effects, harmful effects may also occur. In addition to masking vitamin-B12 deficiency, there is some evidence that folic acid may promote progression of established tumours in laboratory animals and humans. In addition, it has been hypothesized that fortification with folic acid may have further negative effects on cancer through genetic selection. Given the high prevalence of cancer, these potentially harmful effects should also be taken into account in the Dutch debate on the advantages and disadvantages of folic acid fortification
    Interactions of [alpha,beta]-unsaturated carbonyl compounds with the glutathione-related biotransformation system
    Iersel, M.L.P.S. van - \ 1998
    Agricultural University. Promotor(en): P.J. van Bladeren; J.H. Koeman. - S.l. : Van Iersel - ISBN 9789054859086 - 120
    meervoudige resistentie tegen geneesmiddelen - multiple drug resistance

    Introduction
    Modulation of glutathione-related biotransformation steps may play a role in important phenomena as anticarcinogenicity and multidrug resistance. Glutathione-related biotransformation comprises three main aspects i.e. glutathione, the glutathione S-transferases and the multidrug resistance associated protein pump. In Figure 6.1 is shown how the levels and relative activities of these three entities interact.

    The research presented in this thesis focused on the effects of the ubiquitous class ofα,β-unsaturated carbonyl compounds on these glutathione-related processes, especially glutathione S-transferase P1-1, while a secondary aim was to provide insight in the metabolism of these compounds.


    Figure 6.1 Interactions between the three aspects of the glutathione-related biotransformation system.

    Firstly, studies were conducted to expand understanding of the mechanisms of both GST inhibition and glutathione conjugation.

    Secondly, the effects of a series of exogenousα,β-unsaturated carbonyl compounds on the glutathione-related biotransformation were studied in a cellular system, as all three aspects are integrated in such a system and the relative importance of the various steps can be estimated.

    Finally, an important endogenousα,β-unsaturated ketone, prostaglandin A 2 , was selected and its metabolism and effects were studied to emphasise the significance of the glutathione-related metabolism for endogenous compounds and obtain insight into the possible role of GST inhibition in regulation of physiological processes.

    Summary
    To elucidate mechanistic features of the covalent interaction betweenα,β-unsaturated carbonyl compounds and GSTP1-1 and to study the involvement of the cysteine residues in this interaction, investigations were performed with mutants of GSTP1-1 ( chapter 2 ). In these mutants cysteine 47 and/or cysteine 101 were mutated into a serine. Theα,β-unsaturated carbonyl compounds, used in this study, inhibited GSTP1-1 activity, but when both cysteine residues were mutated, almost no inhibition of GSTP1-1 could be observed. Mutation of only the cysteine 47 residue already had the same effect. However, especially high concentrations of theα,β-unsaturated compounds still inhibited the double mutant GSTP1-1 to a certain extent, suggesting that lower reactivity sites in the enzyme can be modified as well. From the compounds studied, ethacrynic acid, acrolein, curcumin, and 4-hydroxy-2-nonenal were the most potent covalent inhibitors. As the compounds used are Michael acceptors, reversal of inhibition of activity by an excess of glutathione was investigated. Only for ethacrynic acid and crotonaldehyde, inhibition could be totally reversed. But inhibition by, for instance, acrolein could not be reversed; experiments using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) showed that covalent cross linking between subunits occurred by acrolein (results not shown), as was demonstrated for eugenol previously (Rompelberg et al ., 1996). For the other compounds used, partial restoration of GSTP1-1 activity was observed, again indicating that reactions with other amino acids or binding places play a role as well.

    The results of this chapter indicate thatα,β-unsaturated carbonyl derivatives inhibit GSTP1-1 irreversibly mainly by binding to the cysteine residues, especially cysteine 47. This covalent inactivation might in particular be important, when glutathione concentrations are low.

    The potential relevance of stereoselective formation of glutathione conjugates ofα,β-unsaturated carbonyl compounds for the actual effects of these compounds led to the investigation of the relative formation of the two diastereoisomers of model compound ethacrynic acid. Ethacrynic acid has become a thoroughly and widely studied compound, lately especially with regard to multidrug resistance (Schultz et al ., 1997; Shen et al ., 1997). Glutathione conjugation of ethacrynic acid leads to the formation of two diastereoisomers, chemically in almost equal amounts (48:52). Although it has been shown that rat GST mu did not catalyse glutathione conjugation stereoselectively (Ploemen et al ., 1993b), human GSTP1-1 is stereospecific for the formation of one diastereoisomer, in this thesis designated as diastereoisomer A. GSTA1-1, but not GSTA1-2 and GSTA2-2 is stereoselective for the same diastereoisomer. No significant deconjugation of the diastereoisomeric mixture or of diastereoisomer A alone could be detected, chemically or upon addition of GSTP1-1; the latter probably due to inhibition of the enzyme. Clearly the equilibrium for glutathione conjugation of ethacrynic acid is strongly in favour of product formation. As a first step to study the role of conjugation in relation to the other glutathione-related aspects, IGR-39 human melanoma cells, containing high levels of GSTP1-1, were exposed to ethacrynic acid. Diastereoisomer A was preferentially produced in the medium. Although this has not yet been proven definitively, this was probably due to the stereoselective formation of diastereoisomer A by GSTP1-1 catalysis rather than stereoselective transport of the conjugates ( chapter 3 ).

    From this chapter it is clear that the chemical and enzyme catalysed equilibria for the reaction between ethacrynic acid and glutathione are strongly in favour of product formation. GSTP1-1 stereospecifically catalyses the glutathione conjugation of ethacrynic acid GSTA1-1 is stereoselective for the same diastereoisomer. Furthermore it was shown that stereoselectivity plays a role in cellular systems.

    As glutathione conjugation and inhibition of GST activity have mainly been studied using cytosol or purified enzymes, a method was developed to investigate modulation of glutathione conjugation in intact IGR-39 human melanoma cells by the quantification of the excretion of S-(2,4-dinitrophenyl)glutathione (DNPSG), the glutathione conjugate of the standard substrate 1-chloro-2,4-dinitrobenzene (CDNB). By investigating intracellular glutathione levels, GST activity and intra- and extracellular DNPSG concentration, some determinants involved in the mechanisms of inhibition of DNPSG excretion could be identified ( chapter 4 ). These mechanisms include depletion of glutathione levels, reversible and irreversible inhibition of glutathione S-transferase activity, and modulation of the efflux of glutathione conjugates by an effect on the multidrug resistance associated protein (MRP) pump.

    Using this assay, a series ofα,β-unsaturated carbonyl compounds were tested for their inhibiting properties of DNPSG excretion. Curcumin, an antioxidant and anticarcinogenic compound, was the most potent inhibitor of DNPSG excretion in these cells, followed by ethacrynic acid. Citral did not show any effect of DNPSG excretion up to 100 mM and acrolein was too toxic to get any effect ( chapter 4 ). The mechanisms of inhibition differed between the variousα,β-unsaturated carbonyl compounds. For curcumin and ethacrynic acid, glutathione depletion, reversible inhibition of GSTs and covalent modification of GSTP1-1 all three play a role in the inhibition of DNPSG excretion. However for trans -2-hexenal and cinnamaldehyde, reversible GST inhibition seems to be the major determinant for its effect. Crotonaldehyde mainly inhibits DNPSG excretion by depleting glutathione, but reversible inhibition does presumably plays a role as well. Curcumin and ethacrynic acid also inhibit the efflux of DNPSG by an effect on the transport of the glutathione conjugate out of the cells, probably by the multidrug resistance associated protein (MRP) pump. Indeed, it has been shown that the glutathione conjugate of EA has an equal efficiency for transport by the MRP pump compared to DNPSG (Zaman et al. , 1996).

    Some of theα,β-unsaturated carbonyl compounds, used in this study, thus inhibit GST avtivity in human melanoma cells. They modulate the glutathione related biotransformation system in these cells in different ways, i.e. glutathione depletion, reversible and irreversible inhibition of GST activity and/or influence on the efflux of glutathione conjugates.

    For the endogenousα,β-unsaturated ketone prostaglandin A 2 a more complete picture of its metabolism and the influence on glutathione-related biotransformation could be obtained, as it was also possible to analyse PGA 2 -glutathione conjugate excretion into the medium during exposure of the cells to PGA 2 . After loading IGR-39 human melanoma cells with [ 3H] glycine and subsequent exposure to PGA 2 , both diastereoisomers of the PGA 2 -glutathione conjugate are excreted into the medium, however with a clear excess of the S-form. Previous work indicates that this is the result of the preferential formation of the S-form by GSTP1-1 that is present in the cells and not from a stereoselectivity in transport (Bogaards et al ., 1997; Evers et al ., 1997). Incubation of IGR-39 human melanoma cells with PGA 2 during 1 or 4 hours clearly influenced the glutathione-related metabolism. After 1 hour exposure, DNPSG excretion was reduced mainly due to inhibition of the efflux of the conjugate. Indeed, it has recently been shown that the glutathione conjugates of PGA 2 have a higher affinity for MRP compared to DNPSG (Evers et al ., 1997). After 4 hours, total DNPSG formation was reduced markedly, resulting from depletion of glutathione and reversible and irreversible inhibition of GSTs; inhibition of efflux then only played a minor role. Although irreversible inhibition already accounted for about 25% of the GST inhibition by PGA 2 , depletion of intracellular GSH with BSO resulted in an even higher level of covalent inactivation. Experiments with purified GSTP1-1 and mutants missing one or two cysteine residues, revealed that this covalent inhibition of GSTP1-1 resulted from the binding of PGA 2 to mainly the cysteine 47 moiety of the enzyme. This inactivation could be totally reversed by an excess of glutathione, indicative of a retro-Michael reaction ( chapter 5 ).

    The results of this chapter again prove that GSTP1-1 might play a role in scavenging alkylating agents especially when GSH concentrations are low, or conversely might serve as a storing or transport protein for physiologically important compounds such as PGA 2 .

    Perspectives
    Both endogenous and exogenousα,β-unsaturated carbonyl compounds thus appear to influence several aspects of the glutathione-related biotransformation system. They are conjugated to glutathione, thereby depleting glutathione and thus influencing the redox status of the cells, which plays a role in regulation of Phase II enzymes (Talalay et al ., 1995; Primiano et al ., 1997). These conjugates usually are less toxic than their parent compounds, but it is also possible that they undergo retro-Michael cleavage, releasing the reactive compound under different circumstances, then also influencing the redox status. The glutathione conjugates themselves are inhibitors of GST activity (product binding) and probably by binding the enzyme, they are transported to efflux pumps such as MRP. Stereoselectivity in the formation of GSH conjugates might influence function and toxicity ofα,β-unsaturated carbonyl compounds. Future studies should be performed to further elucidate the conjugation mechanism and the relevance of stereoselectivity in vivo . One can only speculate about the physiological importance of this phenomenon. Studies with the recently developed GST pi knock-out mice (Henderson et al. , 1996) and MRP knock-out mice (Wijnholds et al ., 1997) could give some useful information.α,β-Unsaturated carbonyl compounds can inhibit GST activity both by competitive inhibition on the active site as well as covalent inactivation on the cysteine residues of the enzyme. This covalent binding is reversible due to retro-Michael reaction and most likely constitutes a functional role as well.

    Man is exposed to substantial amounts of theseα,β-unsaturated carbonyl compounds every day, dependent on life style factors, such as diet, smoking, contact with traffic exhaust. Therefore these findings are of considerable relevance. Especially when considering the total daily exposure to the variousα,β-unsaturated carbonyl compounds, concentrations reached in the body might equal the concentrations used in this study. For instance: acrolein is present in wine up to about 3.8 ppm (70 mM) (Feron et al .,1991); curcumin, the major component of the spice curry, is widely used and consumption for adult Indians is estimated on about 125 mg/day (Opdyke and Letizia, 1983); cinnamaldehyde is present in food up to 700ppm (4.7 mM) (Feron et al ., 1991); adding the additional endogenously producedα,β-unsaturated carbonyl compounds, the combined exposure very likely influences the glutathione-related biotransformation system.

    The fact that endogenousα,β-unsaturated carbonyl compounds as 4-hydroxy-2-nonenal, trans -2-hexenal and prostaglandin A 2 are good covalent inhibitors of GSTP1-1 and that covalent modification occurs intracellularly, supports the assumption, that GSTP1-1 might not only play a role in glutathione conjugation but also has other cellular functions. In this respect one can think of GSTP1-1 as a transport or storage protein for endogenous compounds and/or as a general intracellular scavenging protein for electrophilic agents.

    The suggestion that GSTP1-1 might function as a storage for endogenous compounds, is a commonly accepted function of GSTs in general (Listowsky, 1988). GSTP1-1 is known to have a hydrophobic pocket, which binds fatty acids (Nishihira et al ., 1992). Experiments with fatty acids and human GSTP1-1 revealed that linolenic acid is capable of inhibiting GSTP1-1 activity thereby not affecting covalent modification of GSTP1-1 by ethacrynic acid (unpublished results). This means that it should be possible to bind covalently modified GSTP1-1 on the fatty acid binding site. Interesting possibilities arise when this would be possible with regard to biomonitoring exposure to electrophilic compounds as GSTP1-1 is a major GST present in erythrocytes.

    Closely linked to this storage function, is the possible function of GSTP1-1 as a transport protein. As indicated for prostaglandin A 2 in chapter 5 , GSTP1-1 can transport this compound intracellularly to the nucleus by binding it. Localization of GSTP1-1 in human tissue, using immunohistochemical techniques, indeed show the presence of this isoenzyme in the nucleus (Terrier et al ., 1990). Compounds that are delivered in the nucleus can for instance change thiols, from GST to a transcription factor or other protein and accordingly trigger all sorts of events. It becomes now more and more accepted that genes, involved in protection against carcinogens are regulated by the redox status of cells (Talalay et al ., 1995; Primiano et al ., 1997; Itoh et al ., 1997). Another aspect in the role of GSTP1-1 as a transport protein is the capability of the enzyme to bind products. For instance the glutathione conjugate of ethacrynic acid is an even better inhibitor of GSTP1-1 than the parent compound. One could clearly think of a role of GSTP1-1 in transporting glutathione conjugates from the site of formation to efflux pumps in the plasma membrane, for instance MRP.

    The third notion, that GSTP1-1 might function as a general scavenging protein, might especially be apparent when glutathione levels are low. Lipid peroxidation products as HNE and reactive oxygen species can thus be neutralized, but also other electrophilic compounds. The inactivation of GSTP1-1 by 4-hydroxy-2-nonenal (HNE) and the only partial recovery of activity after incubation with a molar excess of glutathione ( chapter 2 ) are in line with previous findings with H 2 O 2 (Sluis-Cremer et al ., 1996). The ability of otherα,β-unsaturated carbonyl compounds to inactivate purified GSTP1-1 as well as GSTP1-1 in cells ( chapter 2, 4 and 5 ), together with previous results (Berhane and Mannervik, 1990; Terada et al ., 1995) also support a general scavenging role of GSTP1-1.

    The significance of MRP in the maintenance of intracellular concentrations of both functional and toxic or carcinogenic agents is under current investigation. However,α,β-unsaturated carbonyl compounds may influence its transport activity, for a start by depletion of glutathione, which seems to be essential for MRP. Furthermore, as the glutathione conjugates of both EA and PGA 2 are substrates, the glutathione conjugates of otherα,β-unsaturated carbonyl derivates might be substrates as well. Future research should focus on structure activity relationships for MRP substrates. The importance of stereoselectivity in the transport of these conjugates by MRP also merits further investigation (Evers et al ., 1997, Loe et al ., 1997).

    Conclusion
    In conclusion, the results in this thesis demonstrate for the first time that GST activity is inhibited in cells exposed toα,β-unsaturated carbonyl compounds. It also became clear that GST activity should not be studied on its own, but, as it is a part of a glutathione-mediated biotransformation system, it should be investigated in conjunction with glutathione levels and the multidrug resistance associated protein (MRP). Moreover, the apparent involvement of GSTP1-1 in the metabolism of the endogenous compound prostaglandin A 2 , indicates a possible role of this isoenzyme in regulation of cell proliferation. Mostα,β-unsaturated carbonyl compounds, studied in this thesis, interact with the glutathione-related biotransformation system (i.e. glutathione conjugation, glutathione depletion, both reversible and irreversible inhibition of GST activity, modulation of MRP); some with three aspects, some only with one or two. In view of the multiple roles of this system in cellular physiology, cell proliferation, gene regulation, anticarcinogenicity and multidrug resistance,α,β-unsaturated carbonyl compounds indeed seem very important, especially as man is exposed to this class of compounds in everyday life. The results open further perspectives for the development of therapeutic agents regarding multidrug resistance and anticarcinogenicity. The potential effect of these compounds on vital processes emphasise the need for future research on the total exposure of people to these compounds, especially via diet and environment.

    Cancer Prevention by Dietary Constituents in toxicological perspective.
    Verhagen, H. ; Rompelberg, C.J.M. ; Strube, M. ; Poppel, G. van; Bladeren, P.J. van - \ 1997
    Journal of Environmental Pathology, Toxicology and Oncology 16 (1997). - ISSN 0731-8898 - p. 343 - 360.
    Irreversible inhibition of cytosolic glutathione S-transferase.
    Ploemen, J.H.T.M. ; Ommen, B. van; Iersel, M.L.P.S. van; Rompelberg, C.J.M. ; Verhagen, H. ; Bladeren, P.J. van - \ 1996
    In: Glutathione S-transferase: structure, functions and clinical application / Vermeulen, N.P.E., - p. 143 - 152.
    De graslandkalender
    Rompelberg, L.E.M. ; Overvest, J. - \ 1986
    Lelystad : Proefstation voor de Rundveehouderij, Schapenhouderij enPaardenhouderij (Publikatie / Proefstation voor de Rundveehouderij, Schapenhouderij en Paardenhouderij 39) - 44
    graslanden - agrarische bedrijfsvoering - agrarische bedrijfsplanning - grasslands - farm management - farm planning
    De graslandkalender is in de praktijk geontroduceerd in 1974. Daarvoor kwamen allerlei vormen voor die varieerden van een weideboek tot een kastje met mm-papier op rollen. De oude vormen beperkten zich voornamelijk tot registratie. De nieuwe vorm biedt naast de mogelijkheid van registratie ook de mogelijkheid tot planning.
    Normen voor de voedervoorziening
    Rompelberg, L.E.M. ; Wieling, H. ; Overvest, J. - \ 1984
    Lelystad : Proefstation voor de Rundveehouderij, Schapenhouderij enPaardenhouderij (Publikatie / Proefstation voor de Rundveehouderij, Schapenhouderij en Paardenhouderij 23) - 59
    diervoedering - voedingsnormen - voer - graslanden - nederland - animal feeding - feeding standards - feeds - grasslands - netherlands
    In de achter ons liggende jaren zijn er grote veranderingen in de weidebouw en de veevoe-ding geweest. Ook de komende jaren zal op de rundveebedrijven nog veel veranderen. Om hierop in te spelen in voorlichting en onderzoek is de vraag naar normen voor weidebouw en voor veevoeding groot.
    Normen voor de voedervoorziening
    Wieling, H. ; Koops, A.H. ; Rompelberg, L.E.M. ; Jong, S. de - \ 1982
    Lelystad : Proefstation voor de Rundveehouderij (Rapport / Proefstation voor de Rundveehouderij 57) - 56
    diervoedering - plantkunde - rundvee - voer - graslanden - animal feeding - botany - cattle - feeds - grasslands
    Op een bedrijf worden veel beslissingen genomen. Dit wordt met behulp van programmeringen en begrotingen gedaan, daarvoor zijn technische en financiële gegevens nodig. Wat betreft de voedervoorziening werd tot de jaren zeventig gewerkt met de netto zetmeelwaardeproduktie van grasland als aanbod en met de voedernormen van het CVB als behoefte, zonder voldoende rekening te houden met de onderlinge samenhang van deze twee grootheden. Een werkgroep heeft daarom voor kalveren, pinken en melkkoeien een groot aantal graslandgebruiksplannen opgesteld. Voor melkkoeien zijn daarin een aantal gebruiksmogelijkheden als alternatieven voor het bedrijf opgenomen, zoals onbeperkt weiden, beperkt weiden en zomerstalvoedering. Algemene uitgangspunten zijn uitvoerig in dit rapport weergegeven. Hiertoe rekenen we grasgroei, kwaliteit van het gras, verliezen bij de benutting en voederopname en -behoefte van het vee. Ook de bewerking van uitgangspunten tot normen wordt behandeld. Zowel van kalveren, pinken, melkkoeien en een combinatie van kalveren en pinken zijn de verkregen kengetallen aan de hand van een voorbeeld toegelicht. De daarmee verkregen normen zijn in tabellen verwerkt. De wijze waarop deze tabellen zijn samengesteld, is eveneens weergegeven
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