28 results on '"Alexander Cartus"'
Search Results
2. Metabolism of carcinogenic alpha-asarone by human cytochrome P450 enzymes
- Author
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Alexander Cartus and Dieter Schrenk
- Subjects
Population ,Allylbenzene Derivatives ,Anisoles ,Hydroxylation ,03 medical and health sciences ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Cytochrome P-450 Enzyme System ,Humans ,CYP2A6 ,education ,Carcinogen ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,education.field_of_study ,CYP3A4 ,biology ,Cytochrome P450 ,04 agricultural and veterinary sciences ,General Medicine ,040401 food science ,Enzyme ,chemistry ,Biochemistry ,Carcinogens ,Microsomes, Liver ,Microsome ,biology.protein - Abstract
Major metabolites of alpha-asarone in liver microsomes are epoxide-derived side-chain diols. The intermediately formed epoxides are mutagenic and form DNA adducts and thus are likely responsible for the (hepato) carcinogenic effect of alpha-asarone observed in male mice. We here investigated the role of eight human cytochrome P450 enzymes (CYP1A1, 1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4) in the metabolism of alpha-asarone using Supersomes™. The epoxidation of the side-chain of alpha-asarone was mainly catalyzed by CYP3A4 and to a lesser extent by 2B6 and 1A1 whereas the hydroxylation of the side-chain leading to (E)-3'-hydroxyasarone was catalyzed by all investigated CYPs excluding CYP2A6. O-demethylation was catalyzed by CYP1A1, 2A6, 2B6, and 2C19. Applying relative activity factors (RAF) to the observed formation rates revealed that CYP3A4, at least at lower substrate concentrations, is nearly solely responsible for the formation of the mutagenic side-chain epoxides of alpha-asarone. Comparison of the RAF-corrected formation rates of all metabolites with those found in incubation with human liver microsomes revealed that the side-chain hydroxylation and epoxidation can be explained in good approximation by the tested hepatic CYPs, whereas other CYPs or enzymes may contribute to the O-demethylation of alpha-asarone. Therefore, the capacity for metabolic activation of alpha-asarone has to be expected to be widely present among the general population.
- Published
- 2019
3. Toxicodynamic Tests
- Author
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Alexander Cartus and Dieter Schrenk
- Published
- 2020
4. A Benchmark analysis of acrylamide-derived DNA adducts in rat hepatocytes in culture measured by a new, highly sensitive method
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Melanie Hemgesberg, Dieter Schrenk, Simone Stegmüller, and Alexander Cartus
- Subjects
Male ,Acrylamide ,Dose-Response Relationship, Drug ,Metabolism ,Toxicology ,medicine.disease_cause ,Molecular biology ,Rats ,Adduct ,Benchmarking ,DNA Adducts ,chemistry.chemical_compound ,chemistry ,DNA adduct ,Carcinogens ,Hepatocytes ,medicine ,Animals ,Epoxy Compounds ,Rats, Wistar ,Incubation ,DNA ,Genotoxicity ,Carcinogen - Abstract
Acrylamide (AA) is a carcinogen formed during thermal food processing and can cause tumors in rodents while its carcinogenic potency in humans is unclear. Metabolism of AA, preferentially in the liver, leads to glycidamide (GA) forming N7-GA-guanine (N7-GA-Gua) as the major AA-derived DNA adduct in rodents. Here, a novel method allowing high sensitivity by avoidance of major matrix effects was applied to analyze N7-GA-Gua levels in nuclear DNA from rat hepatocytes in primary culture. We could thus for the first time detect a background level of 5-10 adducts/108 nucleosides in untreated hepatocytes. Incubation with AA did not result in a statistically significant increase in adduct levels over background up to a substrate concentration of 500 μM although a trend to slightly higher adduct levels was observed at and above 200 μM AA. At concentrations > 500 μM significant increases in N7-GA-Gua levels were found. When Benchmark concentration (BMC) modeling was applied to the data, non-linear concentration-response curves were obtained suggesting that AA started to cause measurable increases over background of N7-GA-Gua levels above certain concentrations only. Calculation of the composite BMCL10 (Lower Bound of a 95 % confidence interval) of a BMC leading to a 10 % increase of N7-GA-Gua levels over background resulted in a value of 6.35 μM AA after 24 h. A concentration below this value cannot be expected to lead to an increase in N7-GA-Gua of more than 10 % over the background seen in untreated hepatocytes.
- Published
- 2021
5. Acrylamide-derived DNA adducts in human peripheral blood mononuclear cell DNA: Correlation with body mass
- Author
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Simone Stegmüller, Melanie Hemgesberg, Dieter Schrenk, Alexander Cartus, Selina Hemmer, Jean-Pierre Stockis, and Michael Püttmann
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Adult ,Male ,medicine.medical_specialty ,Toxicology ,Peripheral blood mononuclear cell ,Body Mass Index ,Adduct ,DNA Adducts ,Young Adult ,chemistry.chemical_compound ,Internal medicine ,DNA adduct ,medicine ,Humans ,Carcinogen ,Acrylamide ,DNA ,General Medicine ,Middle Aged ,Endocrinology ,chemistry ,Carcinogens ,Leukocytes, Mononuclear ,Female ,Hemoglobin ,Body mass index ,Food Science - Abstract
Acrylamide (AA) is a carcinogen formed during thermal food processing and can cause tumors in rodents while its carcinogenic potency in humans is unclear. Metabolic conversion of AA leads to glycidamide (GA) forming N7-GA-guanine (N7-GA-Gua) as the major DNA adduct in rodents while no such adducts were found in human tissues so far. In a cohort of 56 healthy volunteers adduct levels were determined in peripheral blood mononuclear cell (PBMC) DNA and anthropometric, dietary, and biochemical parameters were measured or inquired using a questionnaire. In the majority of PBMC DNA samples the levels found were above one adduct/108 nucleosides not being correlated to dietary habits including coffee consumption, or to blood glucose levels or hemoglobin HbA1c. However, adduct levels were significantly correlated with the body mass index (BMI) and showed a continuous increase over three BMI classes. Our findings indicate a background of AA-derived DNA adducts present in humans in PBMC related to body mass rather than to certain dietary or lifestyle factors.
- Published
- 2021
6. Current methods in risk assessment of genotoxic chemicals
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Alexander Cartus and Dieter Schrenk
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0301 basic medicine ,Food Contamination ,Toxicology ,medicine.disease_cause ,Risk Assessment ,03 medical and health sciences ,Human health ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Chemical contaminants ,medicine ,Animals ,Humans ,Mycotoxin ,Volume concentration ,Mutagenicity Tests ,04 agricultural and veterinary sciences ,General Medicine ,Contamination ,040401 food science ,Margin of exposure ,030104 developmental biology ,chemistry ,Environmental chemistry ,Environmental science ,Risk assessment ,Hazard Analysis and Critical Control Points ,Genotoxicity ,Mutagens ,Food Science - Abstract
Chemical contaminants and residues are undesired chemicals occurring in consumer products such as food and drugs, at the workplace and in the environment, i.e. in air, soil and water. These compounds can be detected even at very low concentrations and lead frequently to considerable concerns among consumers and in the media. Thus it is a major challenge for modern toxicology to provide transparent and versatile tools for the risk assessment of such compounds in particular with respect to human health. Well-known examples of toxic contaminants are dioxins or mercury (in the environment), mycotoxins (from infections by molds) or acrylamide (from thermal treatment of food). The process of toxicological risk assessment of such chemicals is based on i) the knowledge of their contents in food, air, water etc., ii) the routes and extent of exposure of humans, iii) the toxicological properties of the compound, and, iv) its mode(s) of action. In this process quantitative dose-response relationships, usually in experimental animals, are of outstanding importance. For a successful risk assessment, in particular of genotoxic chemicals, several conditions and models such as the Margin of Exposure (MoE) approach or the Threshold of Toxicological Concern (TTC) concept exist, which will be discussed.
- Published
- 2017
7. Assessment and characterization of DNA adducts produced by alkenylbenzenes in fetal turkey and chicken livers
- Author
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Jian-Dong Duan, Alexander Cartus, Tetyana Kobets, Klaus D. Brunnemann, Simone Stegmüller, Gary M. Williams, Alexander Brengel, and Julia A. Fuhlbrueck
- Subjects
Turkeys ,Toxicology ,medicine.disease_cause ,In ovo ,03 medical and health sciences ,chemistry.chemical_compound ,DNA Adducts ,Structure-Activity Relationship ,0404 agricultural biotechnology ,Fetus ,Methyl eugenol ,medicine ,Benzene Derivatives ,Animals ,Asarone ,Carcinogen ,030304 developmental biology ,0303 health sciences ,Chemistry ,04 agricultural and veterinary sciences ,General Medicine ,040401 food science ,Eugenol ,Biochemistry ,Safrole ,Liver ,Chickens ,Genotoxicity ,DNA ,Food Science - Abstract
Formation of DNA adducts by five alkenylbenzenes, safrole, methyl eugenol, eugenol, and asarone with either α- or β-conformation, was analyzed in fetal avian livers in two in ovo models. DNA reactivity of the carcinogens safrole and methyl eugenol was previously demonstrated in the turkey egg model, whereas non-genotoxic eugenol was negative. In the current study, alkenylbenzenes were also tested in the chicken egg model. Injections with alkenylbenzenes were administered to fertilized turkey or chicken eggs for three consecutive days. Three hours after the last injection, liver samples were evaluated for DNA adduct formation using the 32P-nucleotide postlabeling assay. DNA samples from turkey livers were also analyzed for adducts using mass spectrometry. In both species, genotoxic alkenylbenzenes safrole, methyl eugenol, α- and β-asarone produced DNA adducts, the presence and nature of which, with exception of safrole, were confirmed by mass spectrometry, validating the sensitivity of the 32P-postlabeling assay. Overall, the results of testing were congruent between fetal turkey and chicken livers, confirming that these organisms can be used interchangeably. Moreover, data obtained in both models is comparable to genotoxicity findings in other species, supporting the usefulness of avian models for the assessment of genotoxicity as a potential alternative to animal models.
- Published
- 2019
8. Comparative investigation of the mutagenicity of propenylic and allylic asarone isomers in the Ames fluctuation assay
- Author
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Simone Stegmüller, Roland Bischoff, Dieter Schrenk, Kerstin Berg, and Alexander Cartus
- Subjects
Salmonella typhimurium ,0301 basic medicine ,Allylic rearrangement ,Health, Toxicology and Mutagenesis ,Allylbenzene Derivatives ,Anisoles ,Hydroxylation ,Toxicology ,medicine.disease_cause ,Activation, Metabolic ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Isomerism ,Genetics ,medicine ,Animals ,Asarone ,Genetics (clinical) ,Carcinogen ,Mutagenicity Tests ,food and beverages ,Arylsulfotransferase ,Rats ,030104 developmental biology ,Biochemistry ,chemistry ,030220 oncology & carcinogenesis ,Methyleugenol ,Microsomes, Liver ,Microsome ,Epoxy Compounds ,Estragole ,Genotoxicity ,Mutagens - Abstract
α-, β- and γ-asarone are naturally occurring phenylpropenes that occur in different plant families, mainly in Aristolochiaceae, Acoraceae and Lauraceae. Plants containing asarones are used as flavouring ingredients in alcoholic beverages (bitters), traditional phytomedicines and the rhizome of e.g. Acorus calamus is used to prepare tea. Although α- and β-asarone show a potential in the treatment of several diseases, previous studies have shown carcinogenicity in rodents (duodenum, liver). However, the mechanism of action remained unclear. Studies on the mutagenicity of propenylic α- and β-asarone are inconsistent and data on carcinogenicity and genotoxicity of allylic γ-asarone are lacking completely. Thus, the present study determined the mutagenicity of the three asarone isomers using the Ames fluctuation assay with and without exogenous metabolic activation (S9 mix) in the standard Salmonella typhimurium strains TA98 and TA100. A concentration dependent increase in mutagenicity could be verified for α- and β-asarone in strain TA100 in the presence of rat liver homogenate. The side-chain epoxides of α- and β-asarone, major metabolites formed in liver microsomes, caused mutations in TA100, supporting the hypothesis that epoxidation of the side chain plays a key role in mutagenicity of the propenylic alkenylbenzenes. The allylic γ-asarone, not undergoing detectable side-chain epoxidation in liver microsomes, was supposed to be activated via side-chain hydroxylation and further sulphonation, a typical pathway for other allylic alkenylbenzenes like estragole or methyleugenol. However, neither y-asarone nor 1'-OH-γ-asarone showed any mutagenic effect even in the human SULT-expressing Salmonella strains (TA100-hSULT1A1 and TA100-hSULT1C2), while 1'-OH-methyleugenol used as a positive control was mutagenic under these conditions. These results indicate that the propenylic asarones are genotoxic via metabolic formation of side-chain epoxides while the side-chain hydroxylation/sulphonation pathway is either not operative or does not lead to mutagenicity with the allylic γ-asarone.
- Published
- 2016
9. Metabolism of the carcinogen alpha-asarone in liver microsomes
- Author
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Dieter Schrenk and Alexander Cartus
- Subjects
Male ,0301 basic medicine ,Swine ,Metabolite ,Allylbenzene Derivatives ,Anisoles ,Toxicology ,Hydroxylation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Species Specificity ,Animals ,Humans ,Asarone ,Rats, Wistar ,Phenylpropene ,Mode of action ,Carcinogen ,Molecular Structure ,General Medicine ,Rats ,Kinetics ,Metabolic pathway ,030104 developmental biology ,chemistry ,Biochemistry ,Microsomes, Liver ,Microsome ,Cattle ,Female ,Food Science - 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.
- Published
- 2016
10. Formation and fate of DNA adducts of alpha- and beta-asarone in rat hepatocytes
- Author
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Alexander Cartus, Dieter Schrenk, and Simone Stegmüller
- Subjects
0301 basic medicine ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Allylbenzene Derivatives ,Anisoles ,Toxicology ,Tandem mass spectrometry ,Chemical synthesis ,Adduct ,Ames test ,03 medical and health sciences ,chemistry.chemical_compound ,DNA Adducts ,0302 clinical medicine ,Deoxyadenosine ,Isomerism ,Tandem Mass Spectrometry ,Animals ,Carcinogen ,Chromatography, High Pressure Liquid ,Chemistry ,General Medicine ,Nuclear magnetic resonance spectroscopy ,DNA ,Rats ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hepatocytes ,Food Science - Abstract
While alpha-asarone (aA) and beta-asarone (bA) are genotoxic and were shown to be carcinogenic the mechanisms underlying these effects are not understood. Major metabolites of both compounds are epoxides which are mutagenic in the Ames test. We investigated their reactivity towards nucleosides and identified epoxide-derived DNA adducts with 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) using UPLC-UV/VIS, LC-MS/MS and NMR spectroscopy. The adducts were characterized as N6-1'-hydroxy-dihydro-asarone-dA and N2-1'-hydroxy-dihydro-asarone-dG. Chemical synthesis of these adducts, isotope labeled standards and development of a sensitive and specific isotope dilution mass spectrometric method allowed the quantification of DNA adducts formed in primary rat hepatocytes incubated with aA or bA over up to 48 h. We observed a concentration-dependent, nearly linear formation of DNA adducts, which was higher for bA than for aA. In time course experiments, the amount of DNA adducts reached a maximum within the first 6 h. Over the next 42 h, the amount of DNA adducts decreased, however DNA adducts were still detectable even at the lowest substrate concentration of 10 μM. These results clearly show that aA and bA are able to form epoxide-derived DNA adducts in mammalian cells which may be responsible for their genotoxic, mutagenic and carcinogenic mode of action.
- Published
- 2018
11. Contributors
- Author
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Klaus Abraham, Anton Alldrick, Komala Arsi, Stefan Asam, Diane J. Benford, Marc H.G. Berntssen, Alexander Cartus, Martin Chopra, Benedikt Cramer, Siska Croubels, Els Daeseleire, Dan J. Donoghue, Birgit Dusemund, Melanie Esselen, Alwyn Fernandes, Katharina Habler, Andrea Hartwig, Florian Hübner, Hans-Ulrich Humpf, Gunnar Jahnke, MeeKyung Kim, Thomas Krüger, Maria Lorenzo, Guangyuan Lu, Bernd Luckas, Anne-Katrine Lundebye, Amund Maage, Wolfgang Pfau, Yolanda Pico, Ivonne M.C.M. Rietjens, Karin Röder, Martin Rose, Michael Rychlik, Dieter Schrenk, Albrecht Seidel, David J. Smith, Richard H. Stadler, Viviane Theurillat, Els Van Pamel, Christof Van Poucke, Wen-Xiong Wang, and Carl K. Winter
- Published
- 2018
12. Chemical Contaminants and Residues in Food
- Author
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D Schrenk, Alexander Cartus, D Schrenk, and Alexander Cartus
- Subjects
- Food adulteration and inspection, Food--Toxicology, Food--Analysis, Food contamination
- Abstract
Chemical Contaminants and Residues in Food, Second Edition is an invaluable tool for all industrial and academic researchers involved with food safety, from industry professionals responsible for producing safe food, to chemical analysts involved in testing the final products. This updated edition is expanded to cover the latest research and emerging issues, and has additional information useful for food safety testing. Written by an international team of expert contributors, this edition explores the entire food chain, acting as a roadmap for further research. - Includes expanded coverage on risk assessment and testing technologies - Presents fully updated chapters to provide the most up-to-date information in research on food chemical safety - Provides new information on hot topic areas, such as food additives, mycotoxins, nanomaterials and food contact materials
- Published
- 2017
13. [Plant-derived contaminants in food : Occurrence, effects and risk assessment]
- Author
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Birgit, Dusemund, Ivonne M C M, Rietjens, Alexander, Cartus, Bernd, Schaefer, and Alfonso, Lampen
- Subjects
Germany ,Phytochemicals ,Humans ,Food Contamination ,Dronabinol ,Opium ,Risk Assessment ,Pyrrolizidine Alkaloids ,Tropanes - Abstract
Among the various contaminants, the group of natural plant-derived substances in the modern food chain has been generating increasing concern in recent years. The adverse effects encountered may be diverse and pose risks of acute, subchronic or chronic toxicity. The underlying mechanisms of toxicity may be thresholded or be based on interactions with DNA, as for genotoxic carcinogens, for which the existence of a threshold cannot be assumed. This article gives an overview of the major plant-derived contaminants of present concern in the modern food chain and describes their mode of action and adverse effects.
- Published
- 2017
14. d -Amino Acids and Cross-Linked Amino Acids in Food
- Author
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Alexander Cartus
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Nutritional quality ,Amino acid ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Histidinoalanine ,Organic chemistry ,Food science ,Lysinoalanine ,Racemization ,030217 neurology & neurosurgery ,Lanthionine - Abstract
This chapter covers the process-induced formation of d -amino acids and cross-linked amino acids (CLAAs) in food. The industrial processing of food and feed proteins often includes treatment in heated alkaline or acidic solutions. Such treatments lead to two major chemical changes: formation of CLAAs, such as lysinoalanine, lanthionine, or histidinoalanine, and racemization of free and protein-bound l -amino acids into their d -isomers. Both represent undesired contaminants in food particularly because they diminish the digestibility and nutritional quality of food and may exert toxic properties.
- Published
- 2017
15. Preface
- Author
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Dieter Schrenk and Alexander Cartus
- Published
- 2017
16. Undesired Plant-Derived Components in Food
- Author
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Klaus Abraham, Birgit Dusemund, Dieter Schrenk, Alexander Cartus, and Ivonne M.C.M. Rietjens
- Subjects
0301 basic medicine ,Delta-9-tetrahydrocannabinol ,Toxicology ,Cyanogenic glycosides ,03 medical and health sciences ,Food chain ,0302 clinical medicine ,Furocoumarins ,Phenylpropanoids ,Propenylalkoxybenzenes ,Ethyl carbamate ,Chronic toxicity ,Toxicologie ,Plant-derived contaminants ,VLAG ,Grayanotoxins ,WIMEK ,Opium alkaloids ,Chemistry ,Tropane alkaloids ,Pyrrolizidine alkaloids ,030104 developmental biology ,030220 oncology & carcinogenesis ,Alkenylbenzenes ,Biochemical engineering - Abstract
Among the various chemical compounds, the class of natural plant-derived substances in the modern food chain is generating increasing concern. Adverse effects encountered may be various and pose risks of acute, subchronic, or chronic toxicity. The underlying mechanisms of toxicity may be thresholded, or the contaminants may pose risks because of genotoxicity and carcinogenicity. This chapter gives an overview of the major classes of plant-derived undesired substances including contaminants of present concern in the modern food chain, describing their mode of action and adverse effects.
- Published
- 2017
17. Pflanzliche Kontaminanten in Lebensmitteln : Vorkommen, Wirkung und Risikobewertung
- Author
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Bernd Schaefer, Alfonso Lampen, Ivonne M.C.M. Rietjens, Alexander Cartus, and B. Dusemund
- Subjects
0301 basic medicine ,Opium alkaloids ,Public Health, Environmental and Occupational Health ,Tropane alkaloids ,Biology ,Toxicology ,Pyrrolizidine alkaloids ,03 medical and health sciences ,Food chain ,030104 developmental biology ,0302 clinical medicine ,Environmental health ,Toxicity ,Tetrahydrocannabinol ,030216 legal & forensic medicine ,Risk assessment ,Mode of action ,Adverse effect ,Chronic toxicity ,Toxicologie ,Food contaminant ,VLAG - Abstract
Among the various contaminants, the group of natural plant-derived substances in the modern food chain has been generating increasing concern in recent years. The adverse effects encountered may be diverse and pose risks of acute, subchronic or chronic toxicity. The underlying mechanisms of toxicity may be thresholded or be based on interactions with DNA, as for genotoxic carcinogens, for which the existence of a threshold cannot be assumed. This article gives an overview of the major plant-derived contaminants of present concern in the modern food chain and describes their mode of action and adverse effects.
- Published
- 2017
18. Formation of hepatic DNA adducts by methyleugenol in mouse models: drastic decrease by Sult1a1 knockout and strong increase by transgenic human SULT1A1/2
- Author
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Heinz Himmelbauer, Hansruedi Glatt, Kristin Herrmann, Dieter Schrenk, Klaus E. Appel, Tobias Nolden, Alexander Cartus, Simone Florian, Walter Meinl, and Wolfram Engst
- Subjects
Male ,Cancer Research ,Transgene ,Mice, Transgenic ,Biology ,Polymerase Chain Reaction ,Hydroxylation ,DNA Adducts ,Mice ,chemistry.chemical_compound ,Sulfation ,Deoxyadenosine ,Limit of Detection ,In vivo ,Eugenol ,Animals ,Humans ,DNA Primers ,Mice, Knockout ,chemistry.chemical_classification ,Base Sequence ,Dose-Response Relationship, Drug ,General Medicine ,Arylsulfotransferase ,Molecular biology ,Enzyme ,Liver ,chemistry ,Biochemistry ,Methyleugenol ,Female ,DNA - Abstract
Methyleugenol--a natural constituent of herbs and spices--is hepatocarcinogenic in rodent models. It can form DNA adducts after side-chain hydroxylation and sulfation. We previously demonstrated that human sulfotransferases (SULTs) 1A1 and 1A2 as well as mouse Sult1a1, expressed in Salmonella target strains, are able to activate 1'-hydroxymethyleugenol (1'-OH-ME) and 3'-hydroxymethylisoeugenol (3'-OH-MIE) to mutagens. Now we investigated the role of these enzymes in the formation of hepatic DNA adducts by methyleugenol in the mouse in vivo. We used FVB/N mice [wild-type (wt)] and genetically modified strains in this background: Sult1a1 knockout (ko), transgenic for human SULT1A1/2 (tg) and the combination of both modifications (ko-tg). Methyleugenol (50mg/kg body mass) formed 23, 735, 3770 and 4500 N (2)-(trans-methylisoeugenol-3'-yl)-2'-deoxyguanosine adducts per 10(8) 2'-deoxyribonucleosides (dN) in ko, wt, ko-tg and tg mice, respectively. The corresponding values for an equimolar dose of 1'-OH-ME were 12, 1490, 12 400 and 13 300 per 10(8) dN. Similar relative levels were observed for the minor adduct, N (6)-(trans-methylisoeugenol-3'-yl)-2'-deoxyadenosine. Thus, the adduct formation by both compounds was nearly completely dependent on the presence of SULT1A enzymes, with human SULT1A1/2 producing stronger effects than mouse Sult1a1. Moreover, a dose of 0.05 mg/kg methyleugenol (one-fourth of the estimated average daily exposure of humans) was sufficient to form detectable adducts in humanized (ko-tg) mice. Although 3'-OH-MIE was equally mutagenic to 1'-OH-ME in Salmonella strains expressing human SULT1A1 or 1A2, it only formed 0.14% of hepatic adducts in ko-tg mice compared with an equimolar dose of 1'-OH-ME, suggesting an important role of detoxifying pathways for this isomer in vivo.
- Published
- 2013
19. Plant Polyphenols and Oxidative Metabolites of the Herbal Alkenylbenzene Methyleugenol Suppress Histone Deacetylase Activity in Human Colon Carcinoma Cells
- Author
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Chen Chen, Alexander Cartus, Isabel Anna Maria Groh, Melanie Esselen, and Claudia Lüske
- Subjects
Nutrition and Dietetics ,Article Subject ,Endocrinology, Diabetes and Metabolism ,food and beverages ,Genistein ,Pharmacology ,Isoflavones ,Biology ,HDAC1 ,lcsh:Nutritional diseases. Deficiency diseases ,chemistry.chemical_compound ,chemistry ,Cell culture ,Methyleugenol ,Epigenetics ,Histone deacetylase activity ,Histone deacetylase ,lcsh:RC620-627 ,Research Article ,Food Science - Abstract
Evidence has been provided that diet and environmental factors directly influence epigenetic mechanisms associated with cancer development in humans. The inhibition of histone deacetylase (HDAC) activity and the disruption of the HDAC complex have been recognized as a potent strategy for cancer therapy and chemoprevention. In the present study, we investigated whether selected plant constituents affect HDAC activity or HDAC1 protein status in the human colon carcinoma cell line HT29. The polyphenols (−)-epigallocatechin-3-gallate (EGCG) and genistein (GEN) as well as two oxidative methyleugenol (ME) metabolites were shown to inhibit HDAC activity in intact HT29 cells. Concomitantly, a significant decrease of the HDAC1 protein level was observed after incubation with EGCG and GEN, whereas the investigated ME metabolites did not affect HDAC1 protein status. In conclusion, dietary compounds were found to possess promising HDAC-inhibitory properties, contributing to epigenetic alterations in colon tumor cells, which should be taken into account in further risk/benefit assessments of polyphenols and alkenylbenzenes.
- Published
- 2013
20. Metabolism of Methylisoeugenol in Liver Microsomes of Human, Rat, and Bovine Origin
- Author
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Dieter Schrenk, Karl-Heinz Merz, and Alexander Cartus
- Subjects
Male ,Magnetic Resonance Spectroscopy ,Reactive intermediate ,Pharmaceutical Science ,Anisoles ,Hydroxylation ,High-performance liquid chromatography ,Mass Spectrometry ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Generally recognized as safe ,Animals ,Humans ,Rats, Wistar ,Chromatography, High Pressure Liquid ,Pharmacology ,chemistry.chemical_classification ,Chromatography ,biology ,Cytochrome P450 ,Metabolism ,Rats ,Isoeugenol ,Enzyme ,chemistry ,Biochemistry ,Microsomes, Liver ,biology.protein ,Microsome ,Cattle ,Female ,Metabolic Detoxication, Phase I ,Spectrophotometry, Ultraviolet - Abstract
Methylisoeugenol (1,2-dimethoxy-4-propenylbenzene, 1) is a minor constituent of essential oils, naturally occurring as a mixture of cis/trans isomers. 1 is a U.S. Food and Drug Administration-approved food additive and has been given "Generally Recognized as Safe" status. Previously, metabolism of 1 has been studied in the rat, revealing mainly nontoxic cinnamoyl derivatives as major metabolites. However, data concerning the possible formation of reactive intermediary metabolites are not available to date. In this study, the oxidative metabolism of 1 was studied using liver microsomes of rat [not induced, rat liver microsomes (RLM); Aroclor1254 induced RLM (ARLM)], bovine, and human (pooled from 150 donors) origin. Incubations of these microsomes with 1 provided phase I metabolites that were separated by high-performance liquid chromatography (HPLC) and identified by NMR and UV-visible spectroscopy and/or liquid chromatography-mass spectrometry. Identity was confirmed by comparison with (1)H NMR spectra of synthesized reference compounds. Formation of metabolites was quantified by HPLC/UV using dihydromethyleugenol (10) synthesized as the internal standard. From incubations of ARLM with 1, seven metabolites could be detected, with 3'-hydroxymethylisoeugenol (2), isoeugenol and isochavibetol (3 + 4), and 6-hydroxymethylisoeugenol (5) being the main metabolites. Secondary metabolites derived from 1 were identified as the α,β-unsaturated aldehyde 3'-oxomethylisoeugenol (6) and 1',2'-dihydroxy-dihydromethylisoeugenol (7). We were surprised to find that formation of allylic 6-hydroxymethyleugenol (8) was observed starting at approximately 30 min after the beginning of incubations with ARLM. HLM did not form ring-hydroxylated metabolites but were most active in the formation of 6 and 7. ARLM incubations displayed the highest turnover rate and broadest metabolic pattern, presumably resulting from an increased expression of cytochrome P450 enzymes. In conclusion, we present a virtually complete pattern of nonconjugated microsomal metabolites of 1 comprising reactive metabolites and suggest the formation of reactive intermediates that need more investigation with respect to their possible adverse properties.
- Published
- 2011
21. Microsomal metabolism and mutagenicity of cis- and trans-anethole
- Author
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A. Lencioni, M.J. Carlsson, Alexander Cartus, E.C. Schwind, and J.A. Fuhlbrueck
- Subjects
chemistry.chemical_compound ,chemistry ,Biochemistry ,Microsome ,General Medicine ,Metabolism ,Toxicology ,Anethole ,Cis–trans isomerism - Published
- 2018
22. Hepatic metabolism of carcinogenic β-asarone
- Author
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Alexander Cartus, Nadine Simson, Simone Stegmüller, Sylvia K. Neef, Andrea Wahl, Harald Kelm, and Dieter Schrenk
- Subjects
Male ,Allylbenzene Derivatives ,Rodentia ,Anisoles ,Toxicology ,chemistry.chemical_compound ,medicine ,Animals ,Rats, Wistar ,Mode of action ,Anethole ,Carcinogen ,Chromatography, High Pressure Liquid ,biology ,Cytochrome P450 ,General Medicine ,Rats ,Eugenol ,Metabolic pathway ,chemistry ,Mechanism of action ,Biochemistry ,biology.protein ,Carcinogens ,Microsomes, Liver ,medicine.symptom ,Drug metabolism - Abstract
β-Asarone (1) belongs to the group of naturally occurring phenylpropenes like eugenol or anethole. Compound 1 is found in several plants, e.g., Acorus calamus or Asarum europaeum. Compound 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 and small intestine). The mechanism of action of carcinogenic allylic phenylpropenes consists of the 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 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 rats, bovines, porcines, and humans using (1)H 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 and 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). On the basis of our results, we hypothesize that the genotoxic epoxides of 1 are the ultimate carcinogens formed from 1.
- Published
- 2015
23. Formation of DNA adducts of α- and β-asarone in vitro
- Author
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Simone Stegmüller, Dieter Schrenk, and Alexander Cartus
- Subjects
chemistry.chemical_compound ,Chemistry ,Stereochemistry ,General Medicine ,Toxicology ,β asarone ,DNA ,In vitro ,Adduct - Published
- 2017
24. CYP-inducing potency and metabolism of arylhydrocarbon receptor (AhR)-activating microbial phenazine derivatives (PD)
- Author
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Alexander Cartus, Dieter Schrenk, and R. Schulte Hubbert
- Subjects
chemistry.chemical_compound ,Biochemistry ,Chemistry ,Phenazine ,Potency ,General Medicine ,Metabolism ,Toxicology ,Receptor - Published
- 2016
25. Metabolism of methyleugenol in liver microsomes and primary hepatocytes: pattern of metabolites, cytotoxicity, and DNA-adduct formation
- Author
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Karl-Heinz Merz, Lucas Willi Weishaupt, Dieter Schrenk, Alexander Cartus, Kristin Herrmann, Hansruedi Glatt, and Wolfram Engst
- Subjects
Metabolite ,Secondary metabolite ,Toxicology ,Rats ,chemistry.chemical_compound ,Metabolic pathway ,DNA Adducts ,chemistry ,Biochemistry ,Deoxyadenosine ,Tandem Mass Spectrometry ,Methyleugenol ,Eugenol ,medicine ,Microsome ,Hepatocytes ,Microsomes, Liver ,Deoxyguanosine ,Animals ,Humans ,Cattle ,Oxidation-Reduction ,Carcinogen ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
Methyleugenol (1) is a constituent of many foods, in particular of herbal spices, and is used as flavoring agent in foodstuffs and as fragrance in cosmetics. 1 has been found to be carcinogenic in rodents, its metabolite, 1-hydroxymethyleugenol (2) acting as proximate DNA-binding carcinogen. We incubated 1 with liver microsomes of rat, bovine, and human origin. We found 2, 3-hydroxymethylisoeugenol (3), and 6-hydroxymethyleugenol (4) as major metabolites, and 1-oxomethyleugenol (5), 3-oxomethylisoeugenol (6), eugenol (9), chavibetol (11), and (RS)-2,3-dihydroxy-2,3-dihydromethyleugenol (7) as minor metabolites. Methyleugenol-2,3-epoxide (8), probably the precursor of 7, could not be detected. Incubations with synthetic metabolites were applied in order to uncover metabolic pathways. Incubations with primary rat hepatocytes revealed mainly nonconjugated 2 and conjugated 4, and minor amounts of partly conjugated 7 and conjugated 9 + 11. The "reactive metabolites" 3, 5, 6, and 8 were not detectable, possibly due to rapid reaction with cellular macromolecules. The highest cytotoxicity (resazurin reduction assay and lactate dehydrogenase leakage assay) was observed for the main metabolite 2 and its secondary metabolite 5 with EC(50) values of 50 and 10 µM, respectively. Deoxyadenosine or deoxyguanosine adducts were formed by incubating 1 or metabolites with rat hepatocytes. The rank order of adduct formation was 2 > 1 > 3 > 6, whereas 4, 5, and 8 were inactive. In conclusion, we present a virtually complete pattern of microsomal (rat, bovine, and human) and hepatocellular (rat) metabolites of 1 suggesting the formation of several reactive metabolites possibly involved in carcinogenicity, organ toxicity, and immune reactions.
- Published
- 2012
26. Phase-I-metabolism of asarone-isomers
- Author
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Simone Stegmüller, Alexander Cartus, and Dieter Schrenk
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,Asarone ,General Medicine ,Toxicology ,Drug metabolism - Published
- 2014
27. Toxicological properties of methyleugenol and methylisoeugenol metabolites
- Author
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Isabel Anna Maria Groh, Karl-Heinz Merz, Dieter Schrenk, Kristin Herrmann, Hansruedii Glatt, Lucas Willi Weishaupt, Alexander Cartus, Melanie Esselen, and Wolfram Engst
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Methylisoeugenol ,Chemistry ,Methyleugenol ,Organic chemistry ,General Medicine ,Toxicology - Published
- 2012
28. Comparison of points of departure between subchronic and chronic toxicity studies on food additives, food contaminants and natural food constituents
- Author
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Sabine Guth, Marcel Leist, Alexander Cartus, Barbara E. Engeli, Hans-Georg Joost, Matthias Baum, Alfonso Lampen, Pablo Steinberg, Doris Marko, Angelika Roth, Hans-Ulrich Humpf, Stephanie Hüser, Jan G. Hengstler, Dirk W. Lachenmeier, Gerhard Eisenbrand, Jürg A. Zarn, Angela Mally, and Patrick Diel
- Subjects
food.ingredient ,Food Contamination ,Toxicology ,03 medical and health sciences ,Mice ,0404 agricultural biotechnology ,food ,Subchronic toxicity studies, Chronic toxicity studies, Extrapolation factor, NOAEL, Point of departure, Food constituents ,ddc:570 ,Medicine ,Animals ,Humans ,Toxicity Tests, Chronic ,Chronic toxicity ,030304 developmental biology ,0303 health sciences ,No-Observed-Adverse-Effect Level ,business.industry ,Food additive ,Toxicity Tests, Subchronic ,04 agricultural and veterinary sciences ,General Medicine ,Pesticide ,040401 food science ,Subchronic toxicity ,Prolonged exposure ,Natural food ,Toxicity ,Food Additives ,business ,Food Science ,Food contaminant - Abstract
In the past, it was generally accepted as a default assumption that No-Observed-Adverse-Effect Levels (NOAELs) or Lowest-Observed-Adverse-Effect Levels (LOAELs) in long-term toxicity studies are lower than in short-term ones, i.e. the toxic potency increases with prolonged exposure duration. Recent studies on pesticides and industrial chemicals reported that subacute, subchronic or chronic NOAELs/LOAELs are similar when study design factors are appropriately considered. We investigated whether these findings also apply to certain food constituents. After reviewing subchronic and chronic toxicity studies on more than 100 compounds, a total of 32 compounds could be included in the analysis. Geometric mean (GM) values of subchronic vs. chronic NOAEL or LOAEL ratios ranged from 1.0 to 2.0, with a geometric standard deviation from 2.2 to 4.2, which is consistent with data reported in the literature. While for many of the investigated compounds the ratio is around 1 - suggesting that health-based guidance values could appropriately be derived from subchronic toxicity studies - our study also identified some substances with higher ratios leading to a GM of around 2. The EFSA Scientific Committee suggested to apply an uncertainty factor of 2 to extrapolate from subchronic to chronic studies and, as a precautionary approach, we concur with this suggestion. published
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