103 results found
Akingbasote JA, Foster AJ, Jones HB, et al., 2017, Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid, Toxicology Research, Vol: 6, Pages: 81-88, ISSN: 2045-452X
© The Royal Society of Chemistry. Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit no functional expression of hepatic cytochrome P450 (P450) when compared to wild type (WT) mice, but have normal hepatic and extrahepatic expression of other biotransformation enzymes. We have assessed the utility of HRN™ mice for investigation of the role of metabolic bioactivation in liver toxicity caused by the nonsteroidal anti-inflammatory drug (NSAID) fenclozic acid. In vitro studies revealed significant NADPH-dependent (i.e. P450-mediated) covalent binding of [ 14 C]-fenclozic acid to liver microsomes from WT mice and HRN™ mice, whereas no in vitro covalent binding was observed in the presence of the UDP-glucuronyltransferase cofactor UDPGA. Oral fenclozic acid administration did not alter the liver histopathology or elevate the plasma liver enzyme activities of WT mice, or affect their hepatic miRNA contents. Livers from HRN™ mice exhibited abnormal liver histopathology (enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration, necrosis, inflammatory cell infiltration) and plasma clinical chemistry (elevated alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities). Modest apparent improvements in these abnormalities were observed when HRN™ mice were dosed orally with fenclozic acid for 7 days at 100 mg kg −1 day −1 . Previously we observed more marked effects on liver histopathology and integrity in HRN™ mice dosed orally with the NSAID diclofenac for 7 days at 30 mg kg −1 day −1 . We conclude that HRN™ mice are valuable for assessing P450-related hepatic drug biotransformation, but not for drug toxicity studies due to underlying liver dysfunction. Nonetheless, HRN™ mice may provide novel insights into the role of inflammation in liver injury, thereby aiding its treatment.
Alexander JL, Wilson ID, Teare J, et al., 2017, Gut microbiota modulation of chemotherapy efficacy and toxicity., Nat Rev Gastroenterol Hepatol, Vol: 14, Pages: 356-365
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
Begou O, Gika HG, Wilson ID, et al., 2017, Hyphenated MS-based targeted approaches in metabolomics., Analyst, Vol: 142, Pages: 3079-3100
While global metabolic profiling (untargeted metabolomics) has been the center of much interest and research activity in the past few decades, more recently targeted metabolomics approaches have begun to gain ground. These analyses are, to an extent, more hypothesis-driven, as they focus on a set of pre-defined metabolites and aim towards their determination, often to the point of absolute quantification. The continuous development of the technological platforms used in these studies facilitates the analysis of large numbers of well-characterized metabolites present in complex matrices. The present review describes recent developments in the hyphenated chromatographic methods most often applied in targeted metabolomic/lipidomic studies (LC-MS/MS, CE-MS/MS, and GC-MS/MS), highlighting applications in the life and food/plant sciences. The review also underlines practical challenges-limitations that appear in such approaches.
Glymenaki M, Barnes A, Hagan SO, et al., 2017, Stability in metabolic phenotypes and inferred metagenome profiles before the onset of colitis-induced inflammation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Gray N, Zia R, King A, et al., 2017, High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure, ANALYTICAL CHEMISTRY, Vol: 89, Pages: 2478-2487, ISSN: 0003-2700
P Dickie A, Wilson CE, Schreiter K, et al., 2017, Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel in vivo metabolites, Xenobiotica, Vol: 47, Pages: 538-546, ISSN: 0049-8254
Pickup K, Martin S, Partridge EA, et al., 2017, Acute liver effects, disposition and metabolic fate of [(14)C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice., Arch Toxicol, Vol: 91, Pages: 2643-2653
The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [(14)C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [(14)C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).
Rainville PD, Wilson ID, Nicholson JK, et al., 2017, Ion mobility spectrometry combined with ultra performance liquid chromatography/mass spectrometry for metabolic phenotyping of urine: Effects of column length, gradient duration and ion mobility spectrometry on metabolite detection, ANALYTICA CHIMICA ACTA, Vol: 982, Pages: 1-8, ISSN: 0003-2670
Swann JR, Garcia-Perez I, Braniste V, et al., 2017, Application of H-1 NMR spectroscopy to the metabolic phenotyping of rodent brain extracts: A metabonomic study of gut microbial influence on host brain metabolism, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 143, Pages: 141-146, ISSN: 0731-7085
Triantafyllou E, Pop OT, Possamai LA, et al., 2017, MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure., Gut
OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer(-/-)) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DR(high) cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCII(high) macrophages during the resolution phase in ALF, APAP-treated Mer(-/-) mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DR(high) phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
Wilson ID, Nicholson JK, 2017, Gut microbiome interactions with drug metabolism, efficacy, and toxicity., Transl Res, Vol: 179, Pages: 204-222
The gut microbiota has both direct and indirect effects on drug and xenobiotic metabolisms, and this can have consequences for both efficacy and toxicity. Indeed, microbiome-driven drug metabolism is essential for the activation of certain prodrugs, for example, azo drugs such as prontosil and neoprontosil resulting in the release of sulfanilamide. In addition to providing a major source of reductive metabolizing capability, the gut microbiota provides a suite of additional reactions including acetylation, deacylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, and importantly, in the context of certain types of drug-related toxicity, conjugates hydrolysis reactions. In addition to direct effects, the gut microbiota can affect drug metabolism and toxicity indirectly via, for example, the modulation of host drug metabolism and disposition and competition of bacterial-derived metabolites for xenobiotic metabolism pathways. Also, of course, the therapeutic drugs themselves can have effects, both intended and unwanted, which can impact the health and composition of the gut microbiota with unforeseen consequences.
Goveia J, Pircher A, Conradi LC, et al., 2016, Meta‐analysis of clinical metabolic profiling studies in cancer: challenges and opportunities, EMBO Molecular Medicine, Vol: 8, Pages: 1134-1142, ISSN: 1757-4684
Gray N, Adesina-Georgiadis K, Chekmeneva E, et al., 2016, Development of a Rapid Microbore Metabolic Profiling (RAMMP) UPLC-MS Approach for High-Throughput Phenotyping Studies., Analytical Chemistry, Vol: 88, Pages: 5742-5751, ISSN: 0003-2700
A rapid gradient microbore UPLC-MS method has been developed to provide a high-throughput analytical platform for the metabolic phenotyping of urine from large sample cohorts. The rapid microbore metabolic profiling (RAMMP) approach was based on scaling a conventional reversed-phase UPLC-MS method for urinary profiling from 2.1 x 100 mm columns to 1 x 50 mm columns, increasing the linear velocity of the solvent, and decreasing the gradient time to provide an analysis time of 2.5 min/sample. Comparison showed that conventional UPLC-MS and rapid gradient approaches provided peak capacities of 150 and 50 respectively, with the conventional method detecting approximately 19,000 features compared to the ca. 6000 found using the rapid gradient method. Similar levels of repeatability were seen for both methods. Despite the reduced peak capacity and the reduction in ions detected, the RAMMP method was able to achieve similar levels of group discrimination as conventional UPLC-MS when applied to rat urine samples obtained from investigative studies on the effects of acute 2-bromophenol and chronic acetaminophen administration. When compared to a direct infusion MS method of similar analysis time the RAMMP method provided superior selectivity. The RAMMP approach provides a robust and sensitive method that is well suited to high-throughput metabonomic analysis of complex mixtures such as urine combined with a five fold reduction in analysis time compared with the conventional UPLC-MS method.
Kyriakides M, Maitre L, Stamper BD, et al., 2016, Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer, ARCHIVES OF TOXICOLOGY, Vol: 90, Pages: 3073-3085, ISSN: 0340-5761
Michopoulos F, Karagianni N, Whalley NM, et al., 2016, Targeted Metabolic Profiling of the Tg197 Mouse Model Reveals Itaconic Acid as a Marker of Rheumatoid Arthritis, Journal of Proteome Research, Vol: 15, Pages: 4579-4590, ISSN: 1535-3893
© 2016 American Chemical Society. Rheumatoid arthritis is a progressive, highly debilitating disease where early diagnosis, enabling rapid clinical intervention, would provide obvious benefits to patients, healthcare systems, and society. Novel biomarkers that enable noninvasive early diagnosis of the onset and progression of the disease provide one route to achieving this goal. Here a metabolic profiling method has been applied to investigate disease development in the Tg197 arthritis mouse model. Hind limb extract profiling demonstrated clear differences in metabolic phenotypes between control (wild type) and Tg197 transgenic mice and highlighted raised concentrations of itaconic acid as a potential marker of the disease. These changes in itaconic acid concentrations were moderated or indeed reversed when the Tg197 mice were treated with the anti-hTNF biologic infliximab (10 mg/kg twice weekly for 6 weeks). Further in vitro studies on synovial fibroblasts obtained from healthy wild-type, arthritic Tg197, and infliximab-treated Tg197 transgenic mice confirmed the association of itaconic acid with rheumatoid arthritis and disease-moderating drug effects. Preliminary indications of the potential value of itaconic acid as a translational biomarker were obtained when studies on K4IM human fibroblasts treated with hTNF showed an increase in the concentrations of this metabolite.
Scheer N, Wilson ID, 2016, A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity, DRUG DISCOVERY TODAY, Vol: 21, Pages: 250-263, ISSN: 1359-6446
Sen A, Knappy C, Lewis MR, et al., 2016, Analysis of polar urinary metabolites for metabolic phenotyping using supercritical fluid chromatography and mass spectrometry, JOURNAL OF CHROMATOGRAPHY A, Vol: 1449, Pages: 141-155, ISSN: 0021-9673
Coen M, Wilson ID, 2015, Preclinical Drug Efficacy and Safety Using NMR Spectroscopy, EMAGRES, Vol: 4, Pages: 277-287, ISSN: 2055-6101
Duckett C, McCullagh M, Smith C, et al., 2015, The metabolism of 4-bromoaniline in the bile-cannulated rat: application of ICPMS ((79/81)Br), HPLC-ICPMS & HPLC-oaTOFMS., Xenobiotica, Vol: 45, Pages: 672-680
1. An excretion balance study was performed following i.p. administration of 4-bromoaniline (50 mg kg(-1)) to bile-cannulated rats, using bromine-detected ((79/81)Br) ICPMS for quantification. Approximately 90% of the dose was recovered in urine (68.9 ± 3.6%) and bile (21.4 ± 1.4%) by 48 h post-administration. 2. HPLC-ICPMS ((79/81)Br) was used to selectively detect and profile the major urinary and biliary-excreted metabolites and determined that the 0-12 h urine contained at least 21 brominated metabolites with 19 bromine-containing peaks observed in the 6-12 h bile samples. 3. The urinary and biliary metabolites were subsequently profiled using HPLC-oaTOFMS. By exploiting the distinctive bromine isotope pattern ca. 60 brominated metabolites were detected in the urine in negative electrospray ionisation (ESI) mode while bile contained ca. 21. 4. While a large number of bromine-containing metabolites were detected, the profiles were dominated by a few major components with the bulk of the 4-bromoaniline-related material in urine accounted for by 4-bromoanaline O-sulfate (∼75% of the total by ICPMS, 84% by TOFMS). In bile a hydroxylated N-acetyl compound was the major metabolite detected, forming some ∼65% of the 4-bromoaniline-related material by ICPMS (37% by TOFMS).
Gray N, Lewis MR, Plumb RS, et al., 2015, High-Throughput Microbore UPLC-MS Metabolic Phenotyping of Urine for Large-Scale Epidemiology Studies, JOURNAL OF PROTEOME RESEARCH, Vol: 14, Pages: 2714-2721, ISSN: 1535-3893
Kirchmair J, Goeller AH, Lang D, et al., 2015, Predicting drug metabolism: experiment and/or computation?, NATURE REVIEWS DRUG DISCOVERY, Vol: 14, Pages: 387-404, ISSN: 1474-1776
Rainville PD, Murphy JP, Tomany M, et al., 2015, An integrated ceramic, micro-fluidic device for the LC/MS/MS analysis of pharmaceuticals in plasma, ANALYST, Vol: 140, Pages: 5546-5556, ISSN: 0003-2654
Stahl SH, Yates JW, Nicholls AW, et al., 2015, Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism., Drug Discov Today Technol, Vol: 15, Pages: 9-14
One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach.
Wilson ID, 2015, Metabolic phenotyping by liquid chromatography-mass spectrometry to study human health and disease., Anal Chem, Vol: 87
Yu H, Barrass N, Gales S, et al., 2015, Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey., Xenobiotica, Vol: 45, Pages: 270-277
1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.
Barnes AJ, Baker DR, Hobby K, et al., 2014, Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone, XENOBIOTICA, Vol: 44, Pages: 174-185, ISSN: 0049-8254
Gika HG, Wilson ID, Theodoridis GA, 2014, The Role of Mass Spectrometry in Nontargeted Metabolomics, Comprehensive Analytical Chemistry, Vol: 63, Pages: 213-233, ISSN: 0166-526X
Mass spectrometry has become the major analytical technology with which to perform metabolomics/metabonomics. The intention of this chapter is to provide an overview of the approaches taken for MS-based metabolic profiling. We describe the critical steps in study design, specific technological issues, strategies for data mining, and biomarker identification. The chapter depicts the current state-of-the-art for MS-based metabonomics/metabolomics, highlighting recent developments in chromatographic separation technologies, mass spectrometry, and data treatment. We also emphasize the challenges, limitations, and perspectives of metabolomics research, especially having to do with its application in the life sciences and disease biomarker discovery. © 2014 Elsevier B.V.
Grimsley A, Foster A, Gallagher R, et al., 2014, A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice, BIOCHEMICAL PHARMACOLOGY, Vol: 92, Pages: 701-711, ISSN: 0006-2952
Lees H, Swann J, Poucher SM, et al., 2014, Age and Microenvironment Outweigh Genetic Influence on the Zucker Rat Microbiome, PLOS ONE, Vol: 9, ISSN: 1932-6203
Mitchell SC, Waring RH, Wilson ID, 2014, Ethyl sulphate, a chemically reactive human metabolite of ethanol?, XENOBIOTICA, Vol: 44, Pages: 957-960, ISSN: 0049-8254
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.