- S.J.P.L. Berg van den (1)
- L.F. Berger (1)
- P.J. Bladeren van (3)
- E. Bouwmans (1)
- F.W. Claassen (1)
- N.H.P. Cnubben (1)
- Deepak Dalvie (1)
- T. Delatour (1)
- E. Gremaud (1)
- J. Havlik (1)
- P.J.M. Hendriksen (1)
- S.M.F. Jeurissen (1)
- S.C. Khojasteh (1)
- R. Kiwamoto (1)
- V. Klaus (1)
- H. Loveren van (1)
- Ivonne M.C.M. Rietjens (1)
- M. Marin-Kuan (1)
- Grover Miller (1)
- A. Paini (3)
- A.A.C.M. Peijnenburg (1)
- A. Punt (4)
- I. Rietjens (4)
- I.M.C.M. Rietjens (2)
- B. Schilter (3)
- G. Scholz (3)
- J. Shao (1)
- A. Spenkelink (2)
- E.J.R. Sudhölter (1)
- S. Taylor (1)
- F. Viton (1)
- O.L. Volger (1)
Biotransformation and bioactivation reactions–2016 literature highlights
Khojasteh, S.C. ; Rietjens, Ivonne M.C.M. ; Dalvie, Deepak ; Miller, Grover - \ 2017
Drug Metabolism Reviews 49 (2017)3. - ISSN 0360-2532 - p. 285 - 317.
aldehyde oxidase - bioactivation - Biotransformation - cytochrome P450 - UGT
We are pleased to present a second annual issue highlighting a previous year’s literature on biotransformation and bioactivation. Each contributor to this issue worked independently to review the articles published in 2016 and proposed three to four articles, which he or she believed would be of interest to the broader research community. In each synopsis, the contributing author summarized the procedures, analyses and conclusions as described in the original manuscripts. In the commentary sections, our authors offer feedback and highlight aspects of the work that may not be apparent from an initial reading of the article. To be fair, one should still read the original article to gain a more complete understanding of the work conducted. Most of the articles included in this review were published in Drug Metabolism and Disposition or Chemical Research in Toxicology, but attempts were made to seek articles in 25 other journals. Importantly, these articles are not intended to represent a consensus of the best papers of the year, as we did not want to make any arbitrary standards for this purpose, but rather they were chosen by each author for their notable findings and descriptions of novel metabolic pathways or biotransformations. I am pleased that Drs. Rietjens and Dalvie have again contributed to this annual review. We would like to welcome Grover P Miller as an author for this year’s issue, and we thank Tom Baillie for his contributions to last year’s edition. We have intentionally maintained a balance of authors such that two come from an academic setting and two come from industry. Finally, please drop us a note if you find this review helpful. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. This article is dedicated to Professor Thomas Baillie for his exceptional contributions to the field of drug metabolism.
Transcriptome-based functional classifiers for direct immunotoxicity
Shao, J. ; Berger, L.F. ; Hendriksen, P.J.M. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Volger, O.L. - \ 2014
Archives of Toxicology 88 (2014)3. - ISSN 0340-5761 - p. 673 - 689.
blood mononuclear-cells - gene-expression - cyclin g2 - in-vitro - t-cells - jurkat - toxicogenomics - bioactivation - activation - exposure
Current screening methods for direct immunotoxic chemicals are mainly based on general toxicity studies with rodents. The present study aimed to identify transcriptome- based functional classifiers that can eventually be exploited for the development of in vitro screening assays for direct immunotoxicity. To this end, a toxicogenomics approach was applied in which gene expression changes in human Jurkat lymphoblastic T cells were investigated in response to a wide range of compounds, including direct immunotoxicants, immunosuppressive drugs, and non-immunotoxic control chemicals. On the basis of DNA microarray data previously obtained by the exposure of Jurkat cells to 31 test compounds (Shao et al. in Toxicol Sci 135(2):328–346, 2013), we identified a set of 93 genes, of which 80 were significantly regulated (|numerical ratio| C1.62) by at least three compounds and the other 13 genes were significantly regulated by either one single compound or compound class. A total of 28 most differentially regulated genes were selected for qRT-PCR verification using a training set of 44 compounds consisting of the above-mentioned 31 compounds (23 immunotoxic and 8 non-immunotoxic) and 13 additional immunotoxicants. Good correlation between the results of microarray and qRT-PCR (Pearson’s correlation, R C 0.69) was found for 27 out of the 28 genes. Redundancy analysis of these 27 potential classifiers led to a final set of 25 genes. To assess the performance of these genes, Jurkat cells were exposed to 20 additional compounds (external verification set) followed by qRT-PCR. The classifier set of 25 genes gave a good performance in the external verification: accuracy 85 %, true positive rate (sensitivity) 88 %, and true negative rate (specificity) 67 %. Furthermore, on the basis of the gene ontology annotation of the 25 classifier genes, the immunotoxicants examined in this study could be categorized into distinct functional subclasses. In conclusion, we have identified and validated classifier genes that can be used for the development of an in vitro assay for the identification and initial characterization of hazards for direct immunotoxicity of chemicals and drugs. This assay promises to complement animal-free toxicity testing approaches within the field of direct immunotoxicity.
In vivo validation and physiologically based biokinetic modeling of the inhibition of SULT-mediated estragole DNA adduct formation in the liver of male Sprague-Dawley rats by the basil flavonoid nevadensin
Alhusainy, W. ; Paini, A. ; Berg, J.H.J. van den; Punt, A. ; Scholz, G. ; Schilter, B. ; Bladeren, P.J. van; Taylor, S. ; Adams, T.B. ; Rietjens, I. - \ 2013
Molecular Nutrition & Food Research 57 (2013)11. - ISSN 1613-4125 - p. 1969 - 1978.
naturally-occurring alkenylbenzenes - post-labeling analysis - mouse-liver - intestinal-absorption - metabolic stability - mice - safrole - 1'-hydroxyestragole - bioactivation - sulfotransferases
ScopeThe present work investigates whether the previous observation that the basil flavonoid nevadensin is able to inhibit sulfotransferase (SULT)-mediated estragole DNA adduct formation in primary rat hepatocytes could be validated in vivo. Methods and resultsEstragole and nevadensin were co-administered orally to Sprague-Dawley rats, at a ratio reflecting their presence in basil. Moreover, previously developed physiologically based biokinetic (PBBK) models to study this inhibition in rat and in human liver were refined by including a submodel describing nevadensin kinetics. Nevadensin resulted in a significant 36% reduction in the levels of estragole DNA adducts formed in the liver of rats. The refined PBBK model predicts the formation of estragole DNA adducts in the liver of rat with less than twofold difference compared to in vivo data and suggests more potent inhibition in the liver of human compared to rat due to less efficient metabolism of nevadensin in human liver and intestine. ConclusionGiven the role of the SULT-mediated DNA adduct formation in the hepatocarcinogenicity of estragole, the results of the present study suggest that the likelihood of bioactivation and subsequent adverse effects in rodent bioassays may be lower when estragole is dosed with nevadensin compared to dosing of pure estragole.
Matrix-derived combination effect and risk assessment for estragole from basil-containing plant food supplements (PFS)
Berg, S.J.P.L. van den; Klaus, V. ; Alhusainy, W. ; Rietjens, I. - \ 2013
Food and Chemical Toxicology 62 (2013). - ISSN 0278-6915 - p. 32 - 40.
in-vivo - trans-anethole - rat - 1'-hydroxyestragole - derivatives - mouse - bioactivation - constituents - metabolism - safrole
Basil-containing plant food supplements (PFS) can contain estragole which can be metabolised into a genotoxic and carcinogenic 1'-sulfoxymetabolite. This study describes the inhibition of sulfotransferase (SULT)-mediated bioactivation of estragole by compounds present in basil-containing PFS. Results reveal that PFS consisting of powdered basil material contain other compounds with considerable in vitro SULT-inhibiting activity, whereas the presence of such compounds in PFS consisting of basil essential oil was limited. The inhibitor in powdered basil PFS was identified as nevadensin. Physiologically based kinetic (PBK) modeling was performed to elucidate if the observed inhibitory effects can occur in vivo. Subsequently, risk assessment was performed using the Margin of Exposure (MOE) approach. Results suggest that the consequences of the in vivo matrix-derived combination effect are significant when estragole would be tested in rodent bioassays with nevadensin at ratios detected in PFS, thereby increasing MOE values. However, matrix-derived combination effects may be limited at lower dose levels, indicating that the importance of matrix-derived combination effects for risk assessment of individual compounds should be done on a case-by-case basis considering dose-dependent effects. Furthermore, this study illustrates how PBK modeling can be used in risk assessment of PFS, contributing to further reduction in the use of experimental animals. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
A physiologically based in silico model for trans-2-hexenal detoxicifcation and DNA adduct formation in human including interindividual variation indicates efficient detoxification and a negligible genotoxicity risk
Kiwamoto, R. ; Spenkelink, A. ; Rietjens, I.M.C.M. ; Punt, A. - \ 2013
Archives of Toxicology 87 (2013)9. - ISSN 0340-5761 - p. 1725 - 1737.
pharmacokinetic model - 1,n-2-propanodeoxyguanosine adducts - alpha,beta-unsaturated aldehydes - ethyl acrylate - rats - glutathione - bioactivation - metabolism - vivo - sensitivity
A number of a,ß-unsaturated aldehydes are present in food both as natural constituents and as flavouring agents. Their reaction with DNA due to their electrophilic a,ß-unsaturated aldehyde moiety may result in genotoxicity as observed in some in vitro models, thereby raising a safety concern. A question that remains is whether in vivo detoxification would be efficient enough to prevent DNA adduct formation and genotoxicity. In this study, a human physiologically based kinetic/dynamic (PBK/D) model of trans-2-hexenal (2-hexenal), a selected model a,ß-unsaturated aldehyde, was developed to examine dose-dependent detoxification and DNA adduct formation in humans upon dietary exposure. The kinetic model parameters for detoxification were quantified using relevant pooled human tissue fractions as well as tissue fractions from 11 different individual subjects. In addition, a Monte Carlo simulation was performed so that the impact of interindividual variation in 2-hexenal detoxification on the DNA adduct formation in the population as a whole could be examined. The PBK/D model revealed that DNA adduct formation due to 2-hexenal exposure was 0.039 adducts/108 nucleotides (nt) at the estimated average 2-hexenal dietary intake (0.04 mg 2-hexenal/kg bw) and 0.18 adducts/108 nt at the 95th percentile of the dietary intake (0.178 mg 2-hexenal/kg bw) in the most sensitive people. These levels are three orders of magnitude lower than natural background DNA adduct levels that have been reported in disease-free humans (6.8–110 adducts/108 nt), suggesting that the genotoxicity risk for the human population at realistic dietary daily intakes of 2-hexenal may be negligible.
In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling
Paini, A. ; Punt, A. ; Scholz, G. ; Gremaud, E. ; Spenkelink, A. ; Alink, G.M. ; Schilter, B. ; Bladeren, P.J. van; Rietjens, I. - \ 2012
Mutagenesis 27 (2012)6. - ISSN 0267-8357 - p. 653 - 663.
post-labeling analysis - naturally-occurring alkenylbenzenes - tandem mass-spectrometry - species-differences - drug-metabolism - mouse-liver - 1'-hydroxyestragole - glucuronidation - bioactivation - safrole
Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragoleDNA adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA adduct formation in the liver. In lungs and kidneys DNA adducts were detected at lower levels than in the liver confirming the occurrence of DNA adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragoleDNA adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA adduct formation in human.
A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA adduct formation in primary hepatocytes
Paini, A. ; Punt, A. ; Viton, F. ; Scholz, G. ; Delatour, T. ; Marin-Kuan, M. ; Schilter, B. ; Bladeren, P.J. van; Rietjens, I. - \ 2010
Toxicology and Applied Pharmacology 245 (2010)1. - ISSN 0041-008X - p. 57 - 66.
sensitivity-analysis - risk-assessment - mouse-liver - 1'-hydroxyestragole - safrole - humans - bioactivation - toxicity - 1'-hydroxysafrole - carcinogenicity
Estragole has been shown to be hepatocarcinogenic in rodent species at high-dose levels. Translation of these results into the likelihood of formation of DNA adducts, mutation, and ultimately cancer upon more realistic low-dose exposures remains a challenge. Recently we have developed physiologically based biokinetic (PBBK) models for rat and human predicting bioactivation of estragole. These PBBK models, however, predict only kinetic characteristics. The present study describes the extension of the PBBK model to a so-called physiologically based biodynamic (PBBD) model predicting in vivo DNA adduct formation of estragole in rat liver. This PBBD model was developed using in vitro data on DNA adduct formation in rat primary hepatocytes exposed to 1'-hydroxyestragole. The model was extended by linking the area under the curve for 1'-hydroxyestragole formation predicted by the PBBK model to the area under the curve for 1'-hydroxyestragole in the in vitro experiments. The outcome of the PBBD model revealed a linear increase in DNA adduct formation with increasing estragole doses up to 100 mg/kg bw. Although DNA adduct formation of genotoxic carcinogens is generally seen as a biomarker of exposure rather than a biomarker of response, the PBBD model now developed is one step closer to the ultimate toxic effect of estragole than the PBBK model described previously. Comparison of the PBBD model outcome to available data showed that the model adequately predicts the dose-dependent level of DNA adduct formation. The PBBD model predicts DNA adduct formation at low levels of exposure up to a dose level showing to cause cancer in rodent bioassays, providing a proof of principle for modeling a toxicodynamic in vivo endpoint on the basis of solely in vitro experimental data.
Development of an on-line high performance liquid chromatography detection system for human cytochrome P450 1A2 inhibitors in extracts of natural products
Jeurissen, S.M.F. ; Claassen, F.W. ; Havlik, J. ; Bouwmans, E. ; Cnubben, N.H.P. ; Sudhölter, E.J.R. ; Rietjens, I.M.C.M. ; Beek, T.A. van - \ 2007
Journal of Chromatography. A, Including electrophoresis and other separation methods 1141 (2007)1. - ISSN 0021-9673 - p. 81 - 89.
tandem mass-spectrometry - biochemical detection - catalytic activity - coupled online - enzymes - methyleugenol - metabolism - bioactivation - fluorescence - activation
An on-line HPLC screening method for detection of inhibitors of human cytochrome P450 1A2 in extracts was developed. HPLC separation of extracts is connected to a continuous methoxyresorufin-O-demethylation (MROD) assay in which recombinant human P450 1A2 converts methoxyresorufin to its fluorescent metabolite resorufin. The system was tested with three P450 1A2 inhibitors, for which minimum detectable amounts (MDA) ranging from 0.7 to 9.5 ng were obtained. Analysis of a kava kava and a basil extract showed that the on-line system is applicable to complex mixtures, since in both extracts, peaks with P450 1A2 inhibiting activity were observed