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Jeremy K Nicholson

Publications and source records attributed to Jeremy K Nicholson.

At least 55 records · Page 3Linked to original sources
PubMed2005

Investigation of the metabolic fate of 2-, 3- and 4-bromobenzoic acids in bile-duct-cannulated rats by inductively coupled plasma mass spectrometry and high-performance liquid chromatography/inductively coupled plasma mass spectrometry/electrospray mass spectrometry.

Inductively coupled plasma mass spectrometry (ICPMS) has been used to determine the rate and routes of excretion of bromine following the intraperitoneal administration (50 mg kg(-1)) of 2-, 3- and 4-bromobenzoic acids to male bile-duct-cannulated rats. Analysis of urine and bile for (79/81)Br using ICPMS showed that all three bromobenzoic acids were rapidly excreted (82-98%) within 48 h of dosing, primarily via the urine. High-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC/ICPMS) was then used to obtain metabolite profiles for bile and urine. These profiles revealed that extensive metabolism had taken place, with the unchanged bromobenzoic acids forming a minor part of the total of compound-related material detected. Concomitant MS studies, supplemented by alkaline hydrolysis, enabled the identification of the major metabolite of all three of the bromobenzoic acids as a glycine conjugate. Ester glucuronide conjugates were also identified, but formed only a small proportion of total.

Animals↗
PubMed2005

Biofluid 1H NMR-based metabonomic techniques in nutrition research - metabolic effects of dietary isoflavones in humans.

A metabonomic approach to nutrition research may provide an insight into in vivo mechanisms of action following nutritional intervention. This approach was applied to investigate changes in the (1)H NMR spectral profile of urine collected from controlled dietary intervention studies conducted in premenopausal women before and following soy or miso consumption. The aim of the study was to identify the biochemical effects of a diet rich in soy isoflavones, phytochemicals which are receiving significant attention because of their potential importance to human health and wide bioactivity in vitro. By applying various chemometric techniques to the data the biochemical effects of conjugated and unconjugated isoflavones were determined. The biochemical changes observed suggest that soy isoflavone ingestion had significant effects on several metabolic pathways associated with osmolyte fluctuation and energy metabolism. These biochemical changes were more significant following ingestion of the unconjugated soy isoflavone (miso) diet suggesting that the chemical composition of the isoflavones present in soy-based foods may have an effect on their biological efficacy in vivo. This study describes a novel application for (1)H NMR analysis by determining subtle differences in biochemical profiles following dietary intervention and providing further insight into the mechanisms of action of phytochemicals in vivo.

Diet↗
PubMed2005

Metabonomic deconvolution of embedded toxicity: application to thioacetamide hepato- and nephrotoxicity.

We present here the potential of an integrated metabonomic strategy to deconvolute the biofluid metabolic signatures in experimental animals following multiple organ toxicities, using the well-known hepato- and nephrotoxin, thioacetamide. Male Han-Wistar rats were dosed with thioacetamide (150 mg/kg, n = 25), and urine, plasma, liver, and kidney samples were collected postdose for conventional NMR and magic angle spinning (MAS) NMR spectroscopy. These data were correlated with histopathology and plasma clinical chemistry collected at all time points. 1H MAS NMR data from liver and kidney were related to sequential 1H NMR measurements in urine and plasma using pattern recognition methods. One-dimensional 1H NMR spectra were data-reduced and analyzed using principal components analysis (PCA) to show the time-dependent biochemical variations induced by thioacetamide toxicity. From the eigenvector loadings of the PCA, those regions of the 1H NMR spectra, and hence the combinations of endogenous metabolites marking the main phase of the toxic episode, were identified. The thioacetamide-induced biochemical manifestations included a renal and hepatic lipidosis accompanied by hypolipidaemia; increased urinary excretion of taurine and creatine concomitant with elevated creatine in liver, kidney, and plasma; a shift in energy metabolism characterized by depleted liver glucose and glycogen; reduced urinary excretion of tricarboxylic acid cycle intermediates and raised plasma ketone bodies; increased levels of tissue and plasma amino acids leading to amino aciduria verifying necrosis-enhanced protein degradation and renal dysfunction; and elevated hepatic and urinary bile acids indicating secondary damage to the biliary system. This integrated metabonomic approach has been able to identify the tissue of origin for biomarkers present in the metabolic profiles of biofluids, following the onset and progression of a multiorgan pathology, and as such highlights its potential in the evaluation of embedded toxicity in novel drug candidates.

Amino Acids↗
PubMed2005

Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat.

Hydrazine is a model toxin that induces both hepatotoxic and neurotoxic effects in experimental animals. The direct biochemical effects of hydrazine in kidney, liver, and brain tissue were assessed in male Sprague-Dawley rats using magic angle spinning nuclear magnetic resonance (NMR) spectroscopy. A single dose of hydrazine (90 mg/kg) resulted in changes to the biochemical composition of the liver after 24 h including an increase in triglycerides and beta-alanine, together with a decrease in hepatic glycogen, glucose, choline, taurine, and trimethylamine-N-oxide (TMAO). From histopathology measurements of liver tissue, minimal to mild hepatocyte alteration was observed in all animals at 24 h. The NMR spectra of the renal cortex at 24 h after dosing were dominated by a marked increase in the tissue concentration of 2-aminoadipate (2-AA) and beta-alanine, concomitant with depletions in TMAO, myo-inositol, choline, taurine, glutamate, and lysine. No alteration to the NMR spectral profile of the substantia nigra was observed after hydrazine administration, but perturbations to the relative concentrations of creatine, aspartate, myo-inositol, and N-acetyl aspartate were apparent in the hippocampus of hydrazine-treated animals at 24 h postdose. No overt signs of histopathological toxicity were observed in either the kidney or the brain regions examined. Elevated alanine levels were observed in all tissues indicative of a general inhibition of alanine transaminase activity. By 168 h postdose, NMR spectral profiles of treated rats appeared similar to those of matched controls for all tissue types indicative of recovery from toxic insult.

Administration, Oral↗
PubMed2005

Gut microorganisms, mammalian metabolism and personalized health care.

The mammalian gut microbiota interact extensively with the host through metabolic exchange and co-metabolism of substrates. Such metabolome-metabolome interactions are poorly understood, but might be implicated in the aetiology of many human diseases. In this paper, we assess the importance of the gut microbiota in influencing the disposition, fate and toxicity of drugs in the host, and conclude that appropriate consideration of individual human gut microbial activities will be a necessary part of future personalized health-care paradigms.

Animals↗
PubMed2005

The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements.

The utility of metabonomics in the evaluation of xenobiotic toxicity has been comprehensively assessed by the Consortium for Metabonomic Toxicology (COMET), formed between five major pharmaceutical companies and Imperial College London, UK. The main objectives were to assess methodologies, to generate a metabonomic database using (1)H nuclear magnetic resonance (NMR) spectroscopy of rodent urine and blood serum and to build a predictive expert system for target organ toxicity. The analytic and biologic variation that might arise through the use of metabonomics was evaluated and a high degree of robustness demonstrated. With the completion of 147 studies, the chief deliverables of a curated database of rodent biofluid NMR spectra and computer-based expert systems for the prediction of kidney or liver toxicity in rat and mouse based on the spectral data have been generated, and delivered to the sponsoring companies. The project, with its relatively modest resources, has met and exceeded all of its targets and was judged a resounding success by the sponsoring companies who are, in many cases, already enhancing and making use of the data in their in-house studies.

Animals↗
PubMed2004

Evaluation of metabolic variation in normal rat strains from a statistical analysis of 1H NMR spectra of urine.

NMR spectroscopic and statistical methods have been applied to investigate the biochemical variations within and between two phenotypically normal rat strains. The 600 MHz (1)H NMR spectra of urine were acquired as part of a series of drug toxicity studies from 450 control rat urine samples from each of two strains of laboratory rat (Han Wistar and Sprague Dawley). The spectra were data-reduced to 256 intensity descriptors over a range of delta 0.2-10.0. The spectral variation was analysed both within and between strains in terms of the mean, standard deviation, skewness and kurtosis of each descriptor. It is demonstrated that spectral intensities corresponding to a number of endogenous metabolites do not show Gaussian distributions and there is evidence for bimodality for some metabolites. Additionally, despite the visual similarity of the NMR spectra from the two strains of rat, the descriptor distributions and the statistics derived from them revealed differences in the metabolite profiles, which clearly distinguished the two populations. This work is of value in the determination of biochemical normality and variability, and thus can be used to investigate, and place confidence limits on the biochemical deviations, which arise as a consequence of genetic modification or pathophysiological events.

Animals↗
PubMed2004

Application of inductively coupled plasma mass spectrometry and high-performance liquid chromatography--with parallel electrospray mass spectrometry to the investigation of the disposition and metabolic fate of 2-, 3- and 4-iodobenzoic acids in the rat.

ICP-MS, HPLC-ICP-MS and HPLC-ICP-MS/ESI-MS have been applied to determine the disposition and metabolic fate of 2-, 3- and 4-iodobenzoic acids following intraperitoneal administration at 50 mg kg(-1) to male bile duct cannulated rats. Quantitative excretion balance studies based on the determination of the total iodine content of urine and bile showed that all three iodobenzoic acids were rapidly excreted. Recoveries ranging from 95 to 105% of the administered doses were achieved within 24 h of administration. Metabolite profiles for urine and bile showed extensive metabolism with unchanged iodobenzoic acids forming a minor part of the total. A combination of alkaline hydrolysis and MS enabled the identification of the major metabolites of all three iodobenzoic acids as glycine and ester glucuronide conjugates with very little if any of the parent compounds excreted unchanged.

Animals↗
PubMed2004

Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification.

Schistosomiasis, a chronic and debilitating parasitic disease, affects approximately 200 million people in the developing world and imposes a substantial public health and economic impact. Accurately diagnosing at the individual level, monitoring disease progression, and assessing the impact of pharmacological interventions at the population level are of prime importance for controlling schistosomiasis. Using a Schistosoma mansoni-mouse model, we present a characterization of a parasitic infection by metabolic profiling, employing (1)H NMR spectroscopy and multivariate pattern recognition techniques. We infected 10 mice with 80 S. mansoni cercariae each and collected urine samples 49 and 56 days postinfection. Urine samples were also obtained from 10 uninfected control mice at the same time. The metabolic signature of an S. mansoni infection consists of reduced levels of the tricarboxylic acid cycle intermediates, including citrate, succinate, and 2-oxoglutarate, and increased levels of pyruvate, suggesting stimulated glycolysis. A disturbance of amino acid metabolism was also associated with an S. mansoni infection, as indicated by depletion of taurine, 2-oxoisocaproate, and 2-oxoisovalerate and elevation of tryptophan in the urine. A range of microbial-related metabolites, i.e., trimethylamine, phenylacetylglycine, acetate, p-cresol glucuronide, butyrate, propionate, and hippurate, were also coupled with an S. mansoni infection, indicating disturbances in the gut microbiota. Our work highlights the potential of metabolic profiling to enhance our understanding of biological responses to parasitic infections. It also holds promise as a basis for novel diagnostic tests with high sensitivity and specificity and for improved disease surveillance and control.

Animals↗
PubMed2004

Sample classification based on Bayesian spectral decomposition of metabonomic NMR data sets.

1H NMR spectra of biofluids provides a wealth of biochemical information on the metabolic status of an organism. Through the application of pattern recognition and classification algorithms, the data have been shown to provide information on disease diagnosis and the beneficial and adverse effects of potential therapeutics. Here, a novel approach is described for identifying subsets of spectral patterns in databases of NMR spectra, and it is shown that the intensities of these spectral patterns can be related to the onset and recovery from a toxic lesion in both a time-related and dose-related fashion. These patterns form a new type of combination biomarker for the biological effect under study. The approach is illustrated with a study of liver toxicity in rats using NMR spectra of urine following administration of a model hepatotoxin hydrazine.

Animals↗
PubMed2004

Probing molecular dynamics in chromatographic systems using high-resolution 1H magic-angle-spinning NMR spectroscopy: interaction between p-Xylene and C18-bonded silica.

The exact nature of the interaction between small molecules and chromatographic solid phases has been the subject of much research, but detailed understanding of the molecular dynamics in such systems remains elusive. High-resolution (1)H magic-angle-spinning (MAS) NMR spectroscopy has been applied to the investigation of C18-bonded silica material as used in chromatographic separation techniques together with an adsorbed model analyte, p-xylene. Two distinct p-xylene and water environments were identified within the C18-bonded silica through the measurement of (1)H NMR chemical shifts, T(1) and T(2) relaxation times and diffusion coefficients, including their temperature dependence. The results have been analyzed in terms of two environments, p-xylene within the C18 chains, in slow exchange on the NMR time scale with p-xylene in a more mobile state adsorbed as a layer in close proximity to the C18 particles, but which is distinct from free liquid p-xylene. The techniques used here could have more general applications, including the study of drug molecules bound into phospholipid membranes in micelles or vesicles.

Journal Article↗
PubMed2004

An integrated reverse functional genomic and metabolic approach to understanding orotic acid-induced fatty liver.

In functional genomics, DNA microarrays for gene expression profiling are increasingly being used to provide insights into biological function or pathology. To better understand the significance of the multiple transcriptional changes across a time period, the temporal changes in phenotype must be described. Orotic acid-induced fatty liver disease was investigated at the transcriptional and metabolic levels using microarrays and metabolic profiling in two strains of rats. High-resolution 1H-NMR spectroscopic analysis of liver tissue indicated that Kyoto rats compared with Wistar rats are predisposed to the insult. Metabolite analysis and gene expression profiling following orotic acid treatment identified perturbed metabolic pathways, including those involved in fatty acid, triglyceride, and phospholipid synthesis, beta-oxidation, altered nucleotide, methyl donor, and carbohydrate metabolism, and stress responses. Multivariate analysis and statistical bootstrapping were used to investigate co-responses with transcripts involved in metabolism and stress responses. This reverse functional genomic strategy highlighted the relationship between changes in the transcription of stearoyl-CoA desaturase 1 and those of other lipid-related transcripts with changes in NMR-derived lipid profiles. The results suggest that the integration of 1H-NMR and gene expression data sets represents a robust method for identifying a focused line of research in a complex system.

Administration, Oral↗
PubMed2004

Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse.

Gene chip array (Affymetrix) data from liver tissue and high resolution 1H NMR spectra from intact liver tissue, tissue extracts and plasma have been analyzed to identify biochemical changes arising from hepatotoxicity in mice dosed with acetaminophen. These data sets have been co-interpreted in terms of common metabolic pathways. The principal metabolic changes comprised a decrease in hepatic glucose and glycogen in intact tissue, coupled with an increase in lipid content, with increases in the levels of glucose, pyruvate, acetate and lactate in plasma, and increases in alanine and lactate in the aqueous tissue extracts. Collectively these data provide evidence for an increased rate of hepatic glycolysis. The metabolic observations were consistent with the altered levels of gene expression relating to lipid and energy metabolism in liver which both preceded and were concurrent with the metabolic perturbations. The results show that these two technology platforms together offer a complementary view into cellular responses to toxic processes, providing new insight into the toxic consequences, even for well-studied therapeutic agents such as acetaminophen.

Acetaminophen↗
PubMed2004

Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma.

The 1H nuclear magnetic resonance (NMR) spectra of biological samples, such as blood plasma and tissues, are information rich but data complex owing to superposition of the resonances from a multitude of different chemical entities in multiple-phase compartments, hampering detection and subsequent resonance assignments. To overcome these problems, several spectral-editing NMR experiments are described here, combining spin-relaxation filters (based on T(1), T(rho), and T(2)) with both one-dimensional and two-dimensional (2D) NMR spectroscopy. These techniques enable the separation of NMR resonances based on their relaxation times and allow simplification of the complex spectra. In this paper, the approach is exemplified using a control human blood plasma, which is a complex mixture of proteins, lipoproteins, and small-molecule metabolites. In the case of T(1rho)- and T(2)-edited 2D NMR experiments, a "flip-back" pulse was introduced after the relaxation editing to make the phase cycling of the "relaxation filter" and the 2D NMR part independent, thus enabling easy implementation of the phase-sensitive 2D NMR experiments. These methods also permit much higher receiver gains to be used to reduce digitization error, in particular, for the small resonances, which are sometimes vitally important for metabonomics studies. Both pulse sequences and experimental results are discussed for T(1)-, T(1rho)-, and T(2)-filtered COSY, T(2)-filtered phase-sensitive DQF-COSY, and T(1), T(1rho)-, and T(2)-filtered TOCSY NMR.

Blood Chemical Analysis↗
PubMed2004

Environmental metabonomics: applying combination biomarker analysis in earthworms at a metal contaminated site.

Earthworms were taken across an environmental gradient of metal contamination for ecotoxicology assessment. Both indigenous (Lumbricus rubellus and L. terrestris) and introduced earthworms (Eisenia andrei, exposed in mesh bags) were studied. Changes in the levels of small molecule metabolites in earthworm tissue extracts were analysed by 1H NMR spectroscopy as a means of identifying combination biomarker compounds. Principal components analysis of the NMR spectral data revealed that biochemical changes were induced across the metal contamination gradient. Native worms (L. rubellus) from the most polluted sites were associated with an increase in the relative concentration of maltose; a decrease was also seen in the concentration of an as yet unidentified biomarker compound. Introduced worms (E. andrei) did not show differences to the same extent. Direct integration of the resonances from histidine and 1-methylhistidine showed that relative histidine concentrations were elevated slightly for L. rubellus, confirming the results of earlier mesocosm studies. Conversely, the relative concentrations of both histidine and 1-methylhistidine were greatly reduced by metal contamination in L. terrestris. This study demonstrates the utility of NMR spectroscopy in detecting previously unknown potential biomarkers for ecotoxicity testing and identified maltose as a potential biomarker compound deserving of further study.

Animals↗
PubMed2004

Automatic alignment of individual peaks in large high-resolution spectral data sets.

Pattern recognition techniques are effective tools for reducing the information contained in large spectral data sets to a much smaller number of significant features which can then be used to make interpretations about the chemical or biochemical system under study. Often the effectiveness of such approaches is impeded by experimental and instrument induced variations in the position, phase, and line width of the spectral peaks. Although characterizing the cause and magnitude of these fluctuations could be important in its own right (pH-induced NMR chemical shift changes, for example) in general they obscure the process of pattern discovery. One major area of application is the use of large databases of (1)H NMR spectra of biofluids such as urine for investigating perturbations in metabolic profiles caused by drugs or disease, a process now termed metabonomics. Frequency shifts of individual peaks are the dominant source of such unwanted variations in this type of data. In this paper, an automatic procedure for aligning the individual peaks in the data set is described and evaluated. The proposed method will be vital for the efficient and automatic analysis of large metabonomic data sets and should also be applicable to other types of data.

Animals↗
PubMed2004

Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity.

An increased diversity of therapeutic targets in the pharmaceutical industry in recent years has led to a greater diversity of toxicological effects. This, and the increased pace of drug discovery, leads to a need for new technologies for the rapid elucidation of toxicological mechanisms. As part of an evaluation of the utility of metabonomics in drug safety assessment, 1H NMR spectra were acquired on urine and liver tissue samples obtained from rats administered vehicle or a development compound (MrkA) previously shown to induce hepatotoxicity in several animal species. Multivariate statistical analysis of the urinary NMR data clearly discriminated drug-treated from control animals, due to a depletion in tricarboxylic acid cycle intermediates, and the appearance of medium chain dicarboxylic acids. High-resolution magic angle spinning NMR data acquired on liver samples exhibited elevated triglyceride levels that were correlated with changes in the urinary NMR data. Urinary dicarboxylic aciduria is associated with defective metabolism of fatty acids; subsequent in vitro experiments confirmed that MrkA impairs fatty acid metabolism. The successful application of metabonomics to characterize an otherwise ill-defined mechanism of drug-induced toxicity supports the practicality of this approach for resolving toxicity issues for drugs in discovery and development.

Animals↗