A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat

Punt, Ans; Freidig, Andreas P.; Delatour, Thierry; Scholz, Gabriele; Boersma, Marelle G.; Schilter, Benoı̂t; Bladeren, P.J. van; Rietjens, Ivonne M. C. M.

doi:10.1016/j.taap.2008.04.011

Cited by 79 publications

(156 citation statements)

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“…Model predictions for TC deviated on average less than 40% from experimentally observed values, which is relatively good compared with the current state of the art for PBK models of exogenous substances (26)(27)(28)45 ). This is all the more remarkable because the model was obtained via a relatively straightforward translational adaptation of our previously developed mouse model.…”

Section: Discussionsupporting

confidence: 55%

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

Pas

Woutersen

Ommen

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org these cholesterol modeling studies present models that focus on LDL cholesterol (LDL-C) metabolism in plasma ( 4-6 ) or on cellular cholesterol metabolism ( 7 ). These models do not represent all relevant components of whole body cholesterol homeostasis because they lack reactions such as cholesterol absorption and biosynthesis in organs, which are the reactions targeted by important cholesterol-lowering drugs, such as statins. This implies that the models cannot fully explain how relevant plasma cholesterol-associated biomarkers are infl uenced by these drug interventions.We have, therefore, developed an in silico physiologically based kinetic (PBK) model for plasma cholesterol in the mouse that includes all relevant reactions and that correctly predicts the plasma cholesterol levels of a large variety of mouse strains with gene knockouts related to cholesterol metabolism ( 11 ). The model, of which the structure is given in Fig. 1 , is able to predict HDL cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), and total plasma cholesterol (TC) concentrations ( 12 ) as well as the intra-organ pools representing hepatic free cholesterol (Liv-FC), peripheral cholesterol (Per-C), intestinal cholesterol ester (Int-CE), hepatic cholesterol ester (Liv-CE), and intestinal free cholesterol (Int-FC) in the mouse. A similar model for humans will be of considerable value in predicting effects of drugs and genetic variations on plasma cholesterol concentrations. Therefore, the aim of this work is to adapt our model to a human version.Turnover of cholesterol in humans is quantitatively and qualitatively different from that in mice ( 13 ). Qualitative difference resides mainly in the protein cholesteryl ester In silico modeling has proven to be a useful tool in biology because it allows the study of interspecies variation and regulation of homeostasis and allows the integration of information from various sources ( 1-3 ). There are several modeling efforts on cholesterol ( 4-7 ), an important biomarker for the risk for cardiovascular events ( 8-10 ). Most of Manuscript received 4 September 2012 and in revised form 28 September 2012. Published, JLR Papers in Press, September 29, 2012 DOI 10.1194 A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans Abbreviations: C, cholesterol (sum of FC and CE); CE, cholesterol ester; CETP, cholesterol ester transfer protein; FC, free cholesterol; FH, familial hypercholesterolemia; GWAS, genome-wide association study; PBK, physiologically based kinetic; SC, sensitivity coeffi cient; SLOS, Smith-Lemli-Opitz syndrome; TC, total plasma cholesterol (sum of HDL-C and non-HDL-C).

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Section: Discussionsupporting

confidence: 55%

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

Pas

Woutersen

Ommen

et al. 2012

Journal of Lipid Research

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“…Those reactions were described well with Michaelis-Menten kinetics and the resulting Vmax and Km parameters were scaled to in vivo based on the microsomal or S9 protein content. The interplay of these multiple reactions was integrated in the PBBK model and the simulated concentrations of two estragole metabolites in the rat and human urine were reasonably consistent with the observed in vivo data considering the purpose of the modeling was to evaluate the dose-dependent changes in bioactivation, not to predict the absolute dose metrics (Anthony et al, 1987;Punt et al, 2008Punt et al, , 2009 (Paine et al, 1997). From the risk assessment point of view, other phase I and II enzymes in the GI tract should also be carefully considered in IVIVE.…”

Section: Example Of a Qivive Approach For Toxicity Of A Metabolitementioning

confidence: 78%

“…A couple of publications by Punt and colleagues (Punt et al, 2008(Punt et al, , 2009) present an example of a more sophisticated QI-VIVE approach using metabolism data collected in a number of subcellular fractions. Although the intent of the study was to evaluate the relevance of carcinogenicity of estragole reported in high-dose animal studies to human exposure situations, a similar QIVIVE approach also could be applied for the interpretation of in vitro toxicity assays.…”

Section: Example Of a Qivive Approach For Toxicity Of A Metabolitementioning

confidence: 99%

“…The key metabolism parameters to be estimated were rates of multiple biotransformation reactions that determine the level of carcinogenic species (1-sulfooxyestragole) in the liver. Due to the complexity of metabolism steps involved in formation of the ultimate carcinogenic metabolite of estragole as well as detoxication of parent compound and other intermediate metabolites, the approach using a combination of subcellular fractions along with different cofactors was more valuable for the purpose of their modeling than using a more integrated system such as hepatocytes (Punt et al, 2008(Punt et al, , 2009. By manipulating cofactors such as NADPH, UDPGA, NAD + , and PAPS in the selected in vitro system of microsomes or S9, multiple steps of estragole metabolism mediated by CYPs, UGTs, dehydrogenases, and SULTs, respectively, could be characterized.…”

Section: Example Of a Qivive Approach For Toxicity Of A Metabolitementioning

confidence: 99%

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A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

Basketter

Clewell

Kimber

et al. 2012

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“…For example, methyl eugenol and estragole are thought to only show formation of the rodent proximate carcinogenic metabolite at exposures where detoxifi cation mechanisms are saturated and the metabolic pathway changes. [13,14] The presence of low levels of these components in some essential oils may therefore lead to exposures which are of no concern in longer-term studies, whereas oils that contain high levels of these components may be expected to have similar behaviour to the individual substances themselves. Such cases would need to be considered in the design of studies on these oils.…”

Section: Considerations For Toxicological Studiesmentioning

confidence: 99%

Special Issue 40th ISEO: toxicological challenges for essential oils in REACH

Ellis

2010

Flavour & Fragrance J

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Regulation on the registration, evaluation, authorization and restriction of chemicals (REACH) requires that substances produced or imported at ≥ 1 tonne/year in the European Community (EC) are submitted for registration following a phased-in timetable according to tonnage until 2018. Toxicological and ecotoxicological information is required for submission, along with a risk assessment that considers consumer, occupational and environmental exposures. These requirements apply to natural aromatic extracts (mainly essential oils, but also concretes, resinoids, absolutes, etc.), termed 'natural complex substances' (NCSs), in REACH, and present a unique set of challenges, not only due to the cost and administrative burden for essential oils producers and importers, but also in the approach used for the toxicological evaluation of these oils. Identifi cation of representative specifi cations for the conduct of studies and natural variability of product composition is an important and complex area to resolve, even before studies can begin. Adaptation of toxicological test methods to essential oils and the interpretation of results and use in risk assessment present perhaps the greatest challenge. Alternative test and evaluation strategies for essential oils, based on a components approach, off er the potential for strategic testing in achieving REACH compliance. Diff erent approaches may apply, dependent on whether the NCS, which belongs to the category of substances called UVCB in REACH, is a 'simple' well-defi ned substance, e.g. sweet orange peel oil, or one that is complex in nature and is not usually fully characterized, e.g. vetiver oil. Industry has already started work through REACH consortia and industry association activities, yet further refi nement in the assessment approach and experience in dossier submission and acceptance with the European Chemicals Agency (ECHA) remains a real challenge for essential oils producers and importers.

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A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat

Cited by 79 publications

References 29 publications

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

Special Issue 40th ISEO: toxicological challenges for essential oils in REACH

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