The Experts below are selected from a list of 10701 Experts worldwide ranked by ideXlab platform
J. Kevin Chipman - One of the best experts on this subject based on the ideXlab platform.
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Functional Xenobiotic Metabolism and efflux transporters in trout hepatocyte spheroid cultures
Toxicology research, 2015Co-Authors: Chibuzor Uchea, Stewart F. Owen, J. Kevin ChipmanAbstract:Prediction of Xenobiotic fate in fish is important for the regulatory assessment of chemicals under current legislation. Trout hepatocyte spheroids are a promising in vitro model for this assessment. In this investigation, the gene expression and function for Xenobiotic Metabolism and cellular efflux were characterised. Using fluorescence, transport and real time PCR analysis, the expression and functionality of a variety of genes related to Xenobiotic Metabolism and drug efflux were assessed in a range of trout hepatocyte culture preparations. Significantly greater levels of expression of genes involved in Xenobiotic Metabolism and efflux were measured in spheroids (which have been shown to remain viable in excess of 30 days), compared to hepatocytes cultured using conventional suspension and monolayer culture techniques. A transient decline in the expression of genes related to both Xenobiotic Metabolism and transport was determined during spheroid development, with a subsequent recovery in older spheroids. The most mature spheroids also exhibited an expression profile most comparable to that reported in vivo. Functionality of efflux transporters in spheroids was also demonstrated using fluorescent markers and specific inhibitors. In conclusion, the more physiologically relevant architecture in spheroid cultures provides a high functional integrity in relation to Xenobiotic Metabolism and efflux. Together with the enhanced gene expression and longevity of the model, hepatocytes in spheroid culture may prove to be an accurate alternative model to study the mechanisms of these processes in fish liver and provide an assay to determine the bioaccumulation potential of environmental contaminants.
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Oxidative and conjugative Xenobiotic Metabolism in zebrafish larvae in vivo.
Zebrafish, 2010Co-Authors: Huw S. Jones, Grace H. Panter, Thomas H. Hutchinson, J. Kevin ChipmanAbstract:Abstract As zebrafish larvae are being increasingly applied to toxicity testing, there is a need to understand the potential for Xenobiotic Metabolism by these early life-stage organisms. The expression of genes similar to mammalian cytochromes P450 (CYP) 2B6, CYP3A5, and UDP-glucuronosyl transferase (UGT) 1A1, as well as the zebrafish CYP1A was assessed across embryonic development. Activities toward 7-ethoxyresorufin O-deethylase (EROD assay), 7-ethoxycoumarin O-deethylase (ECOD assay), and octyloxymethylresorufin (OOMR assay) were detected at 96 h postfertilization, as was significant phenolic conjugation in the EROD assay (p
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 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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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.
Sandrine Dubrac - One of the best experts on this subject based on the ideXlab platform.
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enhanced expression of genes related to Xenobiotic Metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris
Journal of Investigative Dermatology, 2018Co-Authors: Stefan Blunder, Sulev Koks, Gea Koks, Ene Reimann, Verena Moosbruggermartinz, Robert Gruber, Matthias Schmuth, Sandrine DubracAbstract:Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to Xenobiotic Metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid Metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to Xenobiotic Metabolism.
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enhanced expression of genes related to Xenobiotic Metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris
Journal of Investigative Dermatology, 2018Co-Authors: Stefan Blunder, Sulev Koks, Gea Koks, Ene Reimann, Verena Moosbruggermartinz, Robert Gruber, Matthias Schmuth, Hubert Hackl, Sandrine DubracAbstract:Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to Xenobiotic Metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid Metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to Xenobiotic Metabolism.
A. P. Kulkarni - One of the best experts on this subject based on the ideXlab platform.
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Role of lipoxygenase in Xenobiotic Metabolism: sulfoxidation of thiobenzamide by purified soybean lipoxygenase.
Research communications in chemical pathology and pharmacology, 1991Co-Authors: A. K. Naidu, A. P. KulkarniAbstract:: Earlier this laboratory recognized lipoxygenase catalyzed reactions as a novel pathway for Xenobiotic Metabolism. To further explore the spectrum of reactions catalyzed by lipoxygenase, sulfoxidation of thiobenzamide was studied. Purified soybean lipoxygenase was found to oxidize thiobenzamide to thiobenzamide sulfoxide in the presence of linoleic acid at a rate of 241 nmoles/min/nmole enzyme. The reaction was dependent upon enzyme, pH, thiobenzamide and linoleic acid concentration. Other polyunsaturated fatty acids namely arachidonic acid, cis, 11, 14-eicosadienoic acid and linolenic acid also supported the sulfoxidation reaction. Nordihydroguaiaretic acid and phenidone, the classical inhibitors of lipoxygenase, significantly blocked the sulfoxidation of thiobenzamide.
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Role of lipoxygenase in Xenobiotic Metabolism: sulfoxidation of thiobenzamide by purified soybean lipoxygenase.
Research communications in chemical pathology and pharmacology, 1991Co-Authors: A. K. Naidu, A. P. KulkarniAbstract:Earlier this laboratory recognized lipoxygenase catalyzed reactions as a novel pathway for Xenobiotic Metabolism. To further explore the spectrum of reactions catalyzed by lipoxygenase, sulfoxidation of thiobenzamide was studied. Purified soybean lipoxygenase was found to oxidize thiobenzamide to thiobenzamide sulfoxide in the presence of linoleic acid at a rate of 241 nmoles/min/nmole enzyme. The reaction was dependent upon enzyme, pH, thiobenzamide and linoleic acid concentration. Other polyunsaturated fatty acids namely arachidonic acid, cis, 11, 14-eicosadienoic acid and linolenic acid also supported the sulfoxidation reaction. Nordihydroguaiaretic acid and phenidone, the classical inhibitors of lipoxygenase, significantly blocked the sulfoxidation of thiobenzamide.
Huw S. Jones - One of the best experts on this subject based on the ideXlab platform.
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oxidative and conjugative Xenobiotic Metabolism in zebrafish larvae in vivo
Zebrafish, 2010Co-Authors: Huw S. Jones, Grace H. Panter, Thomas H. Hutchinson, Kevin J ChipmanAbstract:Abstract As zebrafish larvae are being increasingly applied to toxicity testing, there is a need to understand the potential for Xenobiotic Metabolism by these early life-stage organisms. The expression of genes similar to mammalian cytochromes P450 (CYP) 2B6, CYP3A5, and UDP-glucuronosyl transferase (UGT) 1A1, as well as the zebrafish CYP1A was assessed across embryonic development. Activities toward 7-ethoxyresorufin O-deethylase (EROD assay), 7-ethoxycoumarin O-deethylase (ECOD assay), and octyloxymethylresorufin (OOMR assay) were detected at 96 h postfertilization, as was significant phenolic conjugation in the EROD assay (p < 0.001). The induction of CYP1A, the CYP gene zgc:153269, and UGT1A1 after exposure to Aroclor 1254 (100 μg/L, 24 h) was observed, with significant CYP1A induction (p < 0.01). Aroclor exposure also significantly induced EROD activity (p < 0.005), as did coexposure of α-naphthoflavone in a dose-dependent manner (p < 0.05; 5 and 10 μM exposures). Inhibition of CYP activity by SKF52...
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Oxidative and conjugative Xenobiotic Metabolism in zebrafish larvae in vivo.
Zebrafish, 2010Co-Authors: Huw S. Jones, Grace H. Panter, Thomas H. Hutchinson, J. Kevin ChipmanAbstract:Abstract As zebrafish larvae are being increasingly applied to toxicity testing, there is a need to understand the potential for Xenobiotic Metabolism by these early life-stage organisms. The expression of genes similar to mammalian cytochromes P450 (CYP) 2B6, CYP3A5, and UDP-glucuronosyl transferase (UGT) 1A1, as well as the zebrafish CYP1A was assessed across embryonic development. Activities toward 7-ethoxyresorufin O-deethylase (EROD assay), 7-ethoxycoumarin O-deethylase (ECOD assay), and octyloxymethylresorufin (OOMR assay) were detected at 96 h postfertilization, as was significant phenolic conjugation in the EROD assay (p
