Dieter Schrenk

Technische Universität Kaiserslautern, Kaiserlautern, Rheinland-Pfalz, Germany

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Publications (225)696.4 Total impact

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    Alexander T. Cartus · Dieter Schrenk
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    ABSTRACT: Alpha-asarone (1) is a naturally occurring phenylpropene found in several plants, e.g. Acorus calamus. 1-containing plant materials and essential oils thereof are used for flavoring foods and in many phytopharmaceuticals. 1 has been claimed to have positive pharmacological effects, however, it is carcinogenic in male mice (liver) and probably genotoxic. Since the metabolic pathways of 1 have not been investigated and its carcinogenic mode of action is unknown, we investigated the metabolism of 1 in liver microsomes of rat, bovine, porcine, and human origin using HPLC-DAD and LC-ESI-MS/MS and derived kinetic data on the metabolite formation. The main metabolic pathway was the side-chain hydroxylation leading to (E)-3′-hydroxyasarone (2). Epoxidation of 1 presumably led to (E)-asarone-1′,2′-epoxide (4) which instantly hydrolyzed to form erythro- and threo-configured diols (5b+5a). As a minor reaction O-demethylation of 1 was observed. The metabolite formation showed little species-specific differences with the exception of porcine liver microsomes for which the formation of diols 5b+5a exceeded the formation of alcohol 2. The kinetic parameters imply a dependence of the pattern of metabolite formation from substrate concentration. On the basis of our results and earlier findings we hypothesize the genotoxic epoxide 4 being the ultimate carcinogen metabolically formed from 1.
    Preview · Article · Dec 2015

  • No preview · Article · Oct 2015 · Toxicology Letters
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    ABSTRACT: Beta-asarone ( 1 ) belongs to the group of naturally occurring phenylpropenes like eugenol or anethole. 1 is found in several plants, e.g. Acorus calamus or Asarum europaeum . 1 -containing plant materials and essential oils thereof are used to flavor foods and alcoholic beverages and as ingredients of many drugs in traditional phytomedicines. Although 1 has been claimed to have several positive pharmacological effects, it was found to be genotoxic and carcinogenic in rodents (liver, small intestine). The mechanism of action of carcinogenic allylic phenylpropenes consists of metabolic activation via cytochrome P450 enzymes and sulfotransferases. In vivo experiments suggested that this pathway does not play a major role in the carcinogenicity of the propenylic compound 1 as it is the case for other propenylic compounds, e.g. anethole. Since the metabolic pathways of 1 have not been investigated and its carcinogenic mode of action is unknown, we investigated the metabolism of 1 in liver microsomes of rat, bovine, porcine, and human using 1H-NMR, HPLC-DAD and LC-ESI-MS/MS techniques. We synthesized the majority of identified metabolites which were used as reference compounds for the quantification and final verification of metabolites. Microsomal epoxidation of the side chain of 1 presumably yielded ( Z )-asarone-1',2'-epoxide ( 8a ) which instantly was hydrolyzed to the corresponding erythro- and threo-configurated diols ( 9b, 9a ) and the ketone 2,4,5-trimethoxyphenylacetone ( 13 ). This was the main metabolic pathway in the metabolism of 1 in all investigated liver microsomes. Hydroxylation of the side-chain of 1 led to the formation of three alcohols at total yields of less than 30%: 1'-hydroxyasarone ( 2 ), ( E )- and ( Z )-3'-hydroxyasarone ( 4 , 6 ), with 6 being the mainly formed alcohol and 2 being detectable only in liver microsomes of Aroclor 1254-pretreated rats. Small amounts of 4 and 6 were further oxidized to the corresponding carbonyl compounds ( E )- and ( Z )-3'-oxoasarone ( 5 , 7 ). 1'-oxoasarone ( 3 ) was probably also formed in incubations with 1 , but was not detectable, possibly due to its rapid reaction with nucleophiles. Eventually, three mono- O -demethylated metabolites of 1 were detected in minor concentrations. The time course of metabolite formation and determined kinetic parameters show little species-specific differences in the microsomal metabolism of 1 . Furthermore, the kinetic parameters imply a very low dependence of the pattern of metabolite formation from substrate concentration. In human liver microsomes, 71-75% of 1 will be metabolized via epoxidation, 21-15% via hydroxylation (and further oxidation) and 8-10% via demethylation at lower as well as higher concentrations of 1 , respectively (relative values). Based on our results we hypothesize the genotoxic epoxides of 1 being the ultimate carcinogens formed from 1 .
    No preview · Article · Aug 2015 · Chemical Research in Toxicology
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    ABSTRACT: Gifte im Blick Im Giftlexikon finden Sie ein breites Spektrum toxischer Substanzen aus den Bereichen Naturstoffe, synthetische Verbindungen und Kontaminanten. Ein besonderes Augenmerk richten die Autoren auf molekulare Wirkmechanismen und auf die Auswirkungen chronischer Belastung. Die 6. Lieferung umfasst unter anderem die Mykotoxine Aflatoxin und Fusarientoxin, das missbräuchlich als psychotroper Zusatz zu Spirituosen verwendete Asaron / Kalmusöl, das in Kosmetika, Arzneimitteln und Impfstoffen vorkommende Konservierungsmittel Thiomersal. Das fundierte Nachschlagewerk liefert Apothekern, Ärzten, Biologen, Chemikern, Pharmakologen und Toxikologen seit Jahren verlässliche Daten zu wichtigen Giften.
    Full-text · Book · Aug 2015
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    ABSTRACT: A cereal based beverage was developed by fermentation of wort with the basidiomycete Trametes versicolor. The beverage possessed a fruity, fresh, and slightly floral aroma. The volatiles of the beverage were isolated by liquid-liquid extraction (LLE) and additionally by headspace solid phase microextraction (HS-SPME). The aroma compounds were analyzed by a gas chromatography system equipped with a tandem mass spectrometer and an olfactory detection port (GC-MS/MS-O) followed by aroma (extract) dilution analysis. Thirty-four different odor impressions were perceived and 27 corresponding compounds were identified. Fifteen key odorants with flavor dilution (FD) factors ranging from 8 to 128 were quantitated and their respective odor activity values (OAVs) were calculated. Six key odorants were synthesized de novo by T. versicolor. Furthermore, quantitative changes during the fermentation process were analyzed. To prepare for the market introduction of the beverage, a comprehensive safety assessment was performed.
    Full-text · Article · Jul 2015 · Journal of Agricultural and Food Chemistry
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    ABSTRACT: Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). 18 polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2378-TCDD) were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells, which permitted to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide the numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to ten times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.
    Full-text · Article · Feb 2015 · Chemical Research in Toxicology
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    ABSTRACT: EFSA received a request from the Hellenic Food Authority (EFET) for a scientific opinion on the risk to human health from the presence of nickel (Ni) in food, particularly in vegetables. The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) decided to extend the risk assessment also to drinking water. The reproductive and developmental toxicity in experimental animals was selected as the critical effect for the assessment of chronic effects of Ni. A tolerable daily intake of 2.8 µg Ni/kg body weight (b.w.) per day was derived from a lower 95 % confidence limit for a benchmark dose at 10 % extra risk (BMDL 10) of 0.28 mg/kg b.w. for post-implantation fetal loss in rats. The current dietary exposure to Ni raises concern when considering the mean and 95th percentile chronic exposure levels for all different age groups. The systemic contact dermatitis (SCD) elicited in Ni-sensitive humans after oral exposure to Ni was selected as the critical effect suitable for the assessment of acute effects of Ni. A lowest BMDL 10 of 1.1 µg Ni/kg b.w. was derived for the incidence of SCD following oral exposure to Ni of human volunteers. The CONTAM Panel applied a margin of exposure (MOE) approach and considered an MOE of 10 to be indicative of a low health concern. The MOEs calculated considering the estimated mean and the 95th percentile acute exposure levels were considerably below 10 for all age groups. Overall, the CONTAM Panel concluded that, at the current levels of acute dietary exposure to Ni, there is a concern that Ni-sensitized individuals may develop eczematous flare-up skin reactions. The CONTAM Panel noted the need for mechanistic studies to assess the human relevance of the effects on reproduction and development observed in experimental animals and for additional studies on human absorption of nickel from food, for example in combination with duplicate diet studies.
    Full-text · Technical Report · Jan 2015
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    ABSTRACT: The prototype dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert anti-estrogenic effects via activation of the aryl hydrocarbon receptor (AhR) by interfering with the regulation of estrogen homeostasis and the estrogen receptor α (ERα) signaling pathway. The AhR/ER cross-talk is considered to play a crucial role in TCDD- and E2-dependent mechanisms of carcinogenesis, though the concerted mechanism of action in the liver is not yet elucidated. The present study investigated TCDD's impact on the transcriptional cross-talk between AhR and ERα and its modulation by 17β-estradiol (E2) in the human hepatoma cell line HepG2, which is AhR-responsive but ERα-negative. Transient transfection assays with co-transfection of hERα and supplementation of receptor antagonists showed anti-estrogenic action of TCDD via down-regulation of E2-induced ERα signaling. In contrast, enhancement of AhR signaling dependent on ERα was observed providing evidence for increased cytochrome P450 (CYP) induction to promote E2 metabolism. However, relative mRNA levels of major E2-metabolizing CYP1A1 and 1B1 and the main E2-detoxifying catechol-O-methyltransferase were not affected by the co-treatments. This study provides new evidence of a TCDD-activated AhR-mediated molecular AhR/ERα cross-talk mechanism at transcriptional level via indirect inhibition of ERα and enhanced transcriptional activity of AhR in HepG2 cells.
    Full-text · Article · Dec 2014 · Toxicology Reports
  • Kerstin Berg · Christine Braun · Isabel Krug · Dieter Schrenk
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    ABSTRACT: Ginkgolic acids (GAs) are alkylphenols which can be found in the fruits and leaves of Ginkgo biloba L. (Ginkgoaceae) used in herbal teas, drugs and food supplements. Standardized leaf extracts of Ginkgo biloba are widely used in the therapy of cognitive decline including Alzheimer's diseases. However, GAs are known to have cytotoxic and allergenic potential and are suspected to possess genotoxic properties. Therefore, we examined in this study the cytotoxicity and mutagenicity of three major GAs with different alkyl or alkenyl groups (13:0, 15:1, 17:1). Cytotoxicity was assessed in male Chinese hamster lung fibroblasts (V79 cells) using the resazurin reduction assay. The substances showed concentration dependent cytotoxic effects after 24 h of incubation at concentrations of 50 μM and higher. Mutagenicity was determined by using the Ames fluctuation assay in different Salmonella typhimurium strains (TA97a, TA98, TA100 and TA102) with and without exogenous metabolic activation (S9 mix). Furthermore, we analyzed the mutagenic potency of the three major GAs in V79 cells by performing the hypoxanthine phosphoribosyl transferase (HPRT) assay which detects gene mutations at the hprt locus. None of the mutagenic assays showed any increase in mutagenicity above background. Therefore, these data provide evidence that the GAs tested have some cytotoxic potency but are not mutagenic. Thus, our findings contribute to the risk assessment of preparations containing plant extracts from Ginkgo biloba.
    No preview · Article · Dec 2014 · Toxicology
  • Helena Ufelmannand · Dieter Schrenk
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    ABSTRACT: The hepatotoxic cyclic peptide nodularin (NOD) is produced by the cyanobacteriumnodulariaspumigena in fresh and brackish water lakes, ponds and rivers throughout the world and occurs in variable structures resulting in eight different NODs. NOD has been shown to elicit its hepatotoxicity via inhibition of protein phosphatases (PP) 1 and 2A leading to hyperphosphorylation of vital cellular proteins. This mechanism of action is thought to be associated with the tumour promoting action of NOD in rodent liver. Here, we report on the possible consequences of the inhibition of PP1 and PP2A by NOD to stimulate a dualistic cell response linked to induction of apoptosis and to signals needed for cell proliferation. We determined the concentration-dependent induction of apoptosis and DNA damage after 24 hours of NOD treatment in primary rat hepatocytes in culture. NOD significantly increased caspase activities at > 100 nM. Furthermore, nuclear apoptosis characterised by condensed, fragmented or crescent-shaped cell nuclei in NOD-treated primary rat hepatocytes after 24 h at NOD concentrations from 10 nM upwards and DNA fragmentation at 100 and 200 nM NOD could be shown. Furthermore, we demonstrated a time- and concentration-dependent early increase in phosphorylated ERK1/2, p90RSK, p85S6K, p70S6K as well as p38 and a late induction of the anti-apoptotic Bcl-xL. Consequently, these in vitro data suggest that NOD is able to cause acute cell death and to activate both signals involved in ambivalent apoptosis/proliferation crossroads and late anti-apoptotic events possibly involved in liver tumor promotion under conditions of sustained exposure.
    No preview · Article · Dec 2014 · Toxicology in Vitro
  • Source
    Kerstin Berg · Melanie Esselen · Dieter Schrenk

    Preview · Article · Sep 2014 · Toxicology Letters

  • No preview · Article · Sep 2014 · Toxicology Letters
  • Alexander Cartus · Simone Stegmüller · Dieter Schrenk

    No preview · Conference Paper · Sep 2014
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    ABSTRACT: PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.
    Full-text · Article · Aug 2014 · PLoS ONE
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    ABSTRACT: Chemical structure data and corresponding measured bioactivities of compounds are nowadays easily available from public and commercial databases. However, these databases contain heterogeneous data from different laboratories determined under different protocols and, in addition, sometimes even erroneous entries. In this study, we evaluated the use of data from bioactivity databases for the generation of high quality in-silico models for off-target mediated toxicity as a decision support in early drug discovery and crop-protection research. We chose human acetylcholinesterase (hAChE) inhibition as an exemplary endpoint for our case study. A standardized and thorough quality management routine for input data consisting of more than 2,200 chemical entities from bioactivity databases was established. This procedure finally enables the development of predictive QSAR models based on heterogeneous in-vitro data from multiple laboratories. An extended applicability domain approach was used and regression results were refined by an error estimation routine. Subsequent classification augmented by special consideration of borderline candidates leads to high accuracies in external validation achieving correct predictive classification of 96%. The standardized process described herein is implemented as a (semi)automated workflow and thus easily transferable to other off-targets and assay readouts.
    No preview · Article · Aug 2014 · Journal of Chemical Information and Modeling
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    ABSTRACT: PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.
    Full-text · Article · Aug 2014 · PLoS ONE
  • Nicole Raquet · Dieter Schrenk
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    ABSTRACT: Furocoumarins (FCs) are natural constituents widely occurring in plants used as food or in phytomedicines, cosmetics etc. Some FCs exert dermal photo-toxicity and -genotoxicity when combined with UVA irradiation. For a few congeners, skin tumor formation has been described in humans and laboratory animals. Since almost no information is available on the photo-toxic properties of several congeners, we analyzed the photo-cytotoxic, photo-mutagenic, and photo-clastogenic properties in V79 cells for thirteen naturally occurring FCs, and for the coumarin limettin. Furthermore, nine FC mixtures including one mixture based on the FC pattern of an Angelica archangelica extract were tested in the same assays. We found that the concept of relative potency factors for photo-cytotoxic, -mutagenic, and -clastogenicpotencies of FCs, setting the value for 5-methoxypsoralen at 1.00, was applicable to all congeners tested. The concept was used successfully to describe the photo-toxic properties of binary mixtures of 5- and 8-methoxypsoralen. Furthermore, the photo-genotoxic (photo-mutagenic and -clastogenic) properties of complex FC mixtures comprising up to nine different congeners could be predicted. These data suggest that FCs can differ widely in their photo-toxic and photo-genotoxic properties but show relatively strict additivity with respect to their on target-effects when occurring as complex mixtures.
    No preview · Article · Mar 2014 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association

  • No preview · Conference Paper · Feb 2014

  • No preview · Conference Paper · Feb 2014

  • No preview · Conference Paper · Feb 2014

Publication Stats

9k Citations
696.40 Total Impact Points

Institutions

  • 1998-2015
    • Technische Universität Kaiserslautern
      • • Department of Food Chemistry and Environmental Toxicology
      • • Department of Chemistry
      Kaiserlautern, Rheinland-Pfalz, Germany
  • 2014
    • National Institute for Health and Welfare, Finland
      • Department of Environmental Health
      Helsinki, Southern Finland Province, Finland
  • 2009
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 2000
    • Technische Universität Dresden
      • Institute of Clinical Pharmacology
      Dresden, Saxony, Germany
    • University of Greifswald
      • Clinical Pharmacology Group
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 1999
    • Hochschule Kaiserslautern
      Kaiserlautern, Rheinland-Pfalz, Germany
  • 1991-1998
    • University of Tuebingen
      • Institute of Musicology
      Tübingen, Baden-Württemberg, Germany
  • 1993-1994
    • National Cancer Institute (USA)
      • Laboratory of Experimental Carcinogenesis
      베서스다, Maryland, United States
    • National Institutes of Health
      • Laboratory of Experimental Carcinogenesis
      Maryland, United States