The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Frank J Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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Transgenic mice and metabolomics for study of hepatic Xenobiotic metabolism and toxicity
Expert opinion on drug metabolism & toxicology, 2015Co-Authors: Frank J Gonzalez, Zhong-ze FangAbstract:Introduction: The study of Xenobiotic metabolism and toxicity has been greatly aided by the use of genetically modified mouse models and metabolomics.Areas covered: Gene knockout mice can be used to determine the enzymes responsible for the metabolism of Xenobiotics in vivo and to examine the mechanisms of Xenobiotic-induced toxicity. Humanized mouse models are especially important because there exist marked species differences in the Xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing CYPs and nuclear receptors including the pregnane X receptor, the major regulator of Xenobiotic metabolism and transport were produced. With genetically modified mouse models, metabolomics can determine the metabolic map of many Xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of Xenobiotic toxicity and to find early biomarkers for toxicity.Expert opinion: Metabol...
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Xenobiotic metabolomics: major impact on the metabolome.
Annual review of pharmacology and toxicology, 2011Co-Authors: Caroline H. Johnson, Jeffrey R. Idle, Andrew D. Patterson, Frank J GonzalezAbstract:Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from Xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with Xenobiotic metabolism.
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Xenobiotic Metabolism: A View through the Metabolometer
Chemical research in toxicology, 2010Co-Authors: Andrew D. Patterson, Frank J Gonzalez, Jeffrey R. IdleAbstract:The combination of advanced ultraperformance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of Xenobiotics. Here, a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of the experimental cancer therapeutic agent aminoflavone is presented. In all cases, the metabolic maps of the Xenobiotics were considerably enlarged, providing new insights into their toxicology. The inclusion of transgenic mice permitted unequivocal attribution of individual and often novel metabolic pathways to particular enzymes. Last, a future perspective for Xenobiotic metabolomics is discussed and its impact on the metabolome is described. The studies reviewed here are not specific to the mouse and can be adapted to study Xenobiotic metabolism in any animal species, including humans. The view through the metabolometer is unique and visualizes a metabolic space that contains both established and unknown metabolites of a Xenobiotic, thereby enhancing knowledge of their modes of toxic action.
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CYTOCHROME P450 AND Xenobiotic RECEPTOR HUMANIZED MICE
Annual Review of Pharmacology and Toxicology, 2006Co-Authors: Frank J Gonzalez, Aiming YuAbstract:Most Xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain Xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many Xenobiotics can also activate receptors that in turn induce the expression of genes encoding Xenobiotic-metabolizing enzymes and Xenobiotic transporters. However, there are marked species differences in the way mammals respond to Xenobiotics, which are due in large part to molecular differences in receptors and Xenobiotic-metabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in Xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to Xenobiotics, humanized mice are under development.
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Transgenic models in Xenobiotic metabolism and toxicology.
Toxicology, 2002Co-Authors: Frank J GonzalezAbstract:There exist in animals a large number of enzymes that primarily metabolize Xenobiotics including drugs, toxins and carcinogens. While these enzymes are known to activate or inactivate toxins and carcinogens in vitro, it had not been demonstrated until recently whether they are responsible for the biological effects of these chemicals in intact animal models. In order to determine the biological affects of Xenobiotic-metabolizing enzymes, gene knockout mice were made that lack expression of certain P450s (CYP1A1, CYP1A2, CYP1B1 and CYP2E1), microsomal and cytosolic epoxide hydrolases, and NADPH:quinone oxidoreductase. These mice have no deleterious phenotypes indicating that Xenobiotic-metabolizing enzymes have no direct role in mammalian development and physiological homeostasis even though all the genes and enzymes examined are conserved in mammals. However, in many cases, mice lacking certain Xenobiotic-metabolizing enzymes confer resistance to acute toxicities and chemical carcinogenesis thus demonstrating that these enzymes mediate the deleterious effects of chemicals. The use of Xenobiotic metabolism null animal models to study the mechanisms of actions of toxins and carcinogens will be reviewed.
C. Roland Wolf - One of the best experts on this subject based on the ideXlab platform.
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Xenobiotic receptor humanized mice and their utility
Drug metabolism reviews, 2012Co-Authors: Nico Scheer, C. Roland WolfAbstract:The nuclear receptors pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor alpha have important endogenous functions and are also involved in the induction of drug-metabolizing enzymes and transporters in response to exogenous Xenobiotics. Though not belonging to the same protein family, the Per-Sim-ARNT domain receptor aryl hydrocarbon receptor functionally overlaps with the three nuclear receptors in many aspects and is therefore included in this review. Significant species differences in ligand affinity and biological responses as a result of activation of these receptors have been described. Several Xenobiotic receptor humanized mice have been created to overcome these species differences and to provide in vivo models that are more predictive for human responses. This review provides an overview of the different Xenobiotic receptor humanized mouse models described to date and will summarize how these models can be applied in basic research and improve drug discovery and development. Some of the key applications in the evaluation of drug induction, drug-drug interactions, nongenotoxic carcinogenicity, other toxicity, or efficacy studies are described. We also discuss relevant considerations in the interpretation of such data and potential future directions for the use of Xenobiotic receptor humanized mice.
Andrew D. Patterson - One of the best experts on this subject based on the ideXlab platform.
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The gut microbiome: an orchestrator of Xenobiotic metabolism
Acta pharmaceutica Sinica. B, 2019Co-Authors: Stephanie L. Collins, Andrew D. PattersonAbstract:Microbes inhabiting the intestinal tract of humans represent a site for Xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of Xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut via enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit Xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the Xenobiotic, Xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.
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Xenobiotic metabolomics: major impact on the metabolome.
Annual review of pharmacology and toxicology, 2011Co-Authors: Caroline H. Johnson, Jeffrey R. Idle, Andrew D. Patterson, Frank J GonzalezAbstract:Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from Xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with Xenobiotic metabolism.
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Xenobiotic Metabolism: A View through the Metabolometer
Chemical research in toxicology, 2010Co-Authors: Andrew D. Patterson, Frank J Gonzalez, Jeffrey R. IdleAbstract:The combination of advanced ultraperformance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of Xenobiotics. Here, a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of the experimental cancer therapeutic agent aminoflavone is presented. In all cases, the metabolic maps of the Xenobiotics were considerably enlarged, providing new insights into their toxicology. The inclusion of transgenic mice permitted unequivocal attribution of individual and often novel metabolic pathways to particular enzymes. Last, a future perspective for Xenobiotic metabolomics is discussed and its impact on the metabolome is described. The studies reviewed here are not specific to the mouse and can be adapted to study Xenobiotic metabolism in any animal species, including humans. The view through the metabolometer is unique and visualizes a metabolic space that contains both established and unknown metabolites of a Xenobiotic, thereby enhancing knowledge of their modes of toxic action.
Ivan Couée - One of the best experts on this subject based on the ideXlab platform.
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Physiology and toxicology of hormone-disrupting chemicals in higher plants
Plant Cell Reports, 2013Co-Authors: Ivan Couée, Anne-antonella Serra, Fanny Ramel, Gwenola Gouesbet, Cécile SulmonAbstract:Higher plants are exposed to natural environmental organic chemicals, associated with plant-environment interactions, and Xenobiotic environmental organic chemicals, associated with anthropogenic activities. The effects of these chemicals result not only from interaction with metabolic targets, but also from interaction with the complex regulatory networks of hormone signaling. Purpose-designed plant hormone analogues thus show extensive signaling effects on gene regulation and are as such important for understanding plant hormone mechanisms and for manipulating plant growth and development. Some natural environmental chemicals also act on plants through interference with the perception and transduction of endogenous hormone signals. In a number of cases, bioactive Xenobiotics, including herbicides that have been designed to affect specific metabolic targets, show extensive gene regulation effects, which are more in accordance with signaling effects than with consequences of metabolic effects. Some of these effects could be due to structural analogies with plant hormones or to interference with hormone metabolism, thus resulting in situations of hormone disruption similar to animal cell endocrine disruption by Xenobiotics. These hormone-disrupting effects can be superimposed on parallel metabolic effects, thus indicating that toxicological characterisation of Xenobiotics must take into consideration the whole range of signaling and metabolic effects. Hormone-disruptive signaling effects probably predominate when Xenobiotic concentrations are low, as occurs in situations of residual low-level pollutions. These hormone-disruptive effects in plants may thus be of importance for understanding cryptic effects of low-dosage Xenobiotics, as well as the interactive effects of mixtures of Xenobiotic pollutants.
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Xenobiotic sensing and signalling in higher plants
Journal of Experimental Botany, 2012Co-Authors: Fanny Ramel, Anne-antonella Serra, Cécile Sulmon, Gwenola Gouesbet, Ivan CouéeAbstract:: Anthropogenic changes and chemical pollution confront plant communities with various Xenobiotic compounds or combinations of Xenobiotics, involving chemical structures that are at least partially novel for plant species. Plant responses to chemical challenges and stimuli are usually characterized by the approaches of toxicology, ecotoxicology, and stress physiology. Development of transcriptomics and proteomics analysis has demonstrated the importance of modifications to gene expression in plant responses to Xenobiotics. It has emerged that Xenobiotic effects could involve not only biochemical and physiological disruption, but also the disruption of signalling pathways. Moreover, mutations affecting sensing and signalling pathways result in modifications of responses to Xenobiotics, thus confirming interference or crosstalk between Xenobiotic effects and signalling pathways. Some of these changes at gene expression, regulation and signalling levels suggest various mechanisms of Xenobiotic sensing in higher plants, in accordance with Xenobiotic-sensing mechanisms that have been characterized in other phyla (yeast, invertebrates, vertebrates). In higher plants, such sensing systems are difficult to identify, even though different lines of evidence, involving mutant studies, transcription factor analysis, or comparative studies, point to their existence. It remains difficult to distinguish between the hypothesis of direct Xenobiotic sensing and indirect sensing of Xenobiotic-related modifications. However, future characterization of Xenobiotic sensing and signalling in higher plants is likely to be a key element for determining the tolerance and remediation capacities of plant species. This characterization will also be of interest for understanding evolutionary dynamics of stress adaptation and mechanisms of adaptation to novel stressors.
Nico Scheer - One of the best experts on this subject based on the ideXlab platform.
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Xenobiotic receptor humanized mice and their utility
Drug metabolism reviews, 2012Co-Authors: Nico Scheer, C. Roland WolfAbstract:The nuclear receptors pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor alpha have important endogenous functions and are also involved in the induction of drug-metabolizing enzymes and transporters in response to exogenous Xenobiotics. Though not belonging to the same protein family, the Per-Sim-ARNT domain receptor aryl hydrocarbon receptor functionally overlaps with the three nuclear receptors in many aspects and is therefore included in this review. Significant species differences in ligand affinity and biological responses as a result of activation of these receptors have been described. Several Xenobiotic receptor humanized mice have been created to overcome these species differences and to provide in vivo models that are more predictive for human responses. This review provides an overview of the different Xenobiotic receptor humanized mouse models described to date and will summarize how these models can be applied in basic research and improve drug discovery and development. Some of the key applications in the evaluation of drug induction, drug-drug interactions, nongenotoxic carcinogenicity, other toxicity, or efficacy studies are described. We also discuss relevant considerations in the interpretation of such data and potential future directions for the use of Xenobiotic receptor humanized mice.
