Imperial College London

Emeritus ProfessorJeremyNicholson

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Emeritus Professor of Biological Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 3195j.nicholson Website

 
 
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Assistant

 

Ms Wendy Torto +44 (0)20 7594 3225

 
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Location

 

Office no. 665Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

994 results found

Holmes E, Caddick S, Undon JC, Wilson ID, Kryvawych S, Nicholson JKet al., 1995, <sup>1</sup>H and <sup>2</sup>H NMR spectroscopic studies on the metabolism and biochemical effects of 2-bromoethanamine in the rat, Biochemical Pharmacology, Vol: 49, Pages: 1349-1359, ISSN: 0006-2952

Male Fischer 344 rats were dosed with 2-bromoethanamine hydrobromide (BEA, N = 6) or [1,1,2,2,-2H4]-bromoethanamine hydrobromide (BEA-d4, N = 6) at 150 mg/kg i.p. and urine was collected -24 to 0 hr pre-dose and at 0-2 hr, 2-4 hr, 4-8 hr and 8-12 hr post-dose (p.d.). Urine samples were analysed directly using 500 and 600 MHz 1H NMR and 92.1 MHz 2H NMR spectroscopy. The major observed effect of BEA treatment was the induction of transient elevations in urinary glutaric acid (GTA) and adipic acid (ADA) excretion lasting up to 24 hr p.d. Most of the GTA was excreted in the 0-8 hr p.d. with maximal rates of 100-120 μM/hr for each rat occurring between 4 and 8 hr p.d. in animals treated with BEA or BEA-d4. GTA and ADA were shown to be of endogenous origin as there was no detectable incorporation of the 2H label into either compound following treatment of rats with BEA-d4. Following BEA-treatment there was an initial decrease in the levels of urinary citrate, succinate, 2-oxoglutarate and trimethylamine-N-oxide. A subsequent recovery of citrate and succinate was noted following the onset of medullary nephropathy. The abnormal urinary metabolite profiles were similar to that observed in the urine of humans with glutaric aciduria type II (an inborn error of metabolism) caused by a lack of mitochondrial fatty acyl coenzyme A dehydrogenases indicating that BEA or its metabolites have similar metabolic consequences. The BEA metabolite aziridine was detected by 1H and 2H NMR spectroscopy of the urine 8 hr p.d. together with BEA itself and two novel metabolites 2-oxazolidone (OX) and 5-hydroxy-2-oxazolidone (HOX). The formation of OX requires the reaction of BEA with endogenous bicarbonate followed by a cyclisation reaction eliminating HBr. Dosing rats with authentic OX resulted in the excretion of HOX but did not cause glutaric or adipic aciduria indicating that either aziridine or BEA itself was responsible for the presumed defect in mitochondrial metabolism. © 1995.

Journal article

NICHOLLS AW, CADDICK S, WILSON ID, FARRANT RD, LINDON JC, NICHOLSON JKet al., 1995, HIGH-RESOLUTION NMR SPECTROSCOPIC STUDIES ON THE METABOLISM AND FUTILE DEACETYLATION OF 4-HYDROXYACETANILIDE (PARACETAMOL) IN THE RAT, BIOCHEMICAL PHARMACOLOGY, Vol: 49, Pages: 1155-1164, ISSN: 0006-2952

Journal article

LIU M, FARRANT RD, SWEATMAN BC, NICHOLSON JK, LINDON JCet al., 1995, OBSERVATION OF SEPARATE J-RESOLVED H-1-NMR SPECTRA FROM CH, CH2, AND CH3 GROUPS USING A MAXIMUM-QUANTUM FILTER, JOURNAL OF MAGNETIC RESONANCE SERIES A, Vol: 113, Pages: 251-256, ISSN: 1064-1858

Journal article

GLEN RC, PAYNE AWR, 1995, A GENETIC ALGORITHM FOR THE AUTOMATED GENERATION OF MOLECULES WITHIN CONSTRAINTS, JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, Vol: 9, Pages: 181-202, ISSN: 0920-654X

Journal article

ANTHONY ML, ROSE VS, NICHOLSON JK, LINDON JCet al., 1995, CLASSIFICATION OF TOXIN-INDUCED CHANGES IN H-1-NMR SPECTRA OF URINE USING AN ARTIFICIAL NEURAL-NETWORK, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 13, Pages: 205-211, ISSN: 0731-7085

Journal article

Nicholson JK, Foxall PJ, Spraul M, Farrant RD, Lindon JCet al., 1995, 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma., Anal Chem, Vol: 67, Pages: 793-811, ISSN: 0003-2700

High-resolution 750 MHz 1H NMR spectra of control human blood plasma have been measured and assigned by the concerted use of a range of spin-echo, two-dimensional J-resolved, and homonuclear and heteronuclear (1H-13C) correlation methods. The increased spectral dispersion and sensitivity at 750 MHz enable the assignment of numerous 1H and 13C resonances from many molecular species that cannot be detected at lower frequencies. This work presents the most comprehensive assignment of the 1H NMR spectra of blood plasma yet achieved and includes the assignment of signals from 43 low M(r) metabolites, including many with complex or strongly coupled spin systems. New assignments are also provided from the 1H and 13C NMR signals from several important macromolecular species in whole blood plasma, i.e., very-low-density, low-density, and high-density lipoproteins, albumin, and alpha 1-acid glycoprotein. The temperature dependence of the one-dimensional and spin-echo 750 MHz 1H NMR spectra of plasma was investigated over the range 292-310 K. The 1H NMR signals from the fatty acyl side chains of the lipoproteins increased substantially with temperature (hence also molecular mobility), with a disproportionate increase from lipids in low-density lipoprotein. Two-dimensional 1H-13C heteronuclear multiple quantum coherence spectroscopy at 292 and 310 K allowed both the direct detection of cholesterol and choline species bound in high-density lipoprotein and the assignment of their signals and confirmed the assignment of most of the lipoprotein resonances.

Journal article

LIU M, FARRANT RD, NICHOLSON JK, LINDON JCet al., 1995, SELECTIVE DETECTION OF H-1-NMR RESONANCES OF CHN GROUPS USING A HETERONUCLEAR MAXIMUM-QUANTUM FILTER AND PULSED-FIELD GRADIENTS, JOURNAL OF MAGNETIC RESONANCE SERIES B, Vol: 106, Pages: 270-278, ISSN: 1064-1866

Journal article

NICHOLSON JK, FOXALL PJD, SPRAUL M, FARRANT RD, LINDON JCet al., 1995, 750-MHZ H-1 AND H-1-C-13 NMR-SPECTROSCOPY OF HUMAN BLOOD-PLASMA, ANALYTICAL CHEMISTRY, Vol: 67, Pages: 793-811, ISSN: 0003-2700

Journal article

LIU M, FARRANT RD, LINDON JC, NICHOLSON JKet al., 1995, 2-DIMENSIONAL H-1-H-1 AND C-13-H-1 MAXIMUM-QUANTUM CORRELATION NMR-SPECTROSCOPY WITH APPLICATION TO THE ASSIGNMENT OF THE NMR-SPECTRA OF THE BILE-SALT SODIUM TAUROCHOLATE, MAGNETIC RESONANCE IN CHEMISTRY, Vol: 33, Pages: 212-219, ISSN: 0749-1581

Journal article

LIU M, FARRANT RD, NICHOLSON JK, LINDON JCet al., 1995, SELECTIVE DETECTION OF H-1-NMR RESONANCES OF (CHN)-C-13 GROUPS USING 2-DIMENSIONAL MAXIMUM-QUANTUM CORRELATION SPECTROSCOPY, JOURNAL OF MAGNETIC RESONANCE SERIES A, Vol: 112, Pages: 208-219, ISSN: 1064-1858

Journal article

JONES G, WILLETT P, GLEN RC, 1995, MOLECULAR RECOGNITION OF RECEPTOR-SITES USING A GENETIC ALGORITHM WITH A DESCRIPTION OF DESOLVATION, JOURNAL OF MOLECULAR BIOLOGY, Vol: 245, Pages: 43-53, ISSN: 0022-2836

Journal article

Anthony ML, Holmes E, McDowell PCR, Gray TJB, Blackmore M, Nicholson JKet al., 1995, <sup>1</sup>H NMR Spectroscopic Studies on the Reactions of Haloalkylamines with Bicarbonate Ions: Formation of N-Carbamates and 2-Oxazolidones in Cell Culture Media and Blood Plasma, Chemical Research in Toxicology, Vol: 8, Pages: 1046-1053, ISSN: 0893-228X

1H NMR spectroscopic methods have been applied to compare the in vitro reactivity of the renal papillary nephrotoxin 2-bromoethanamine (BEA) with those of selected halide-substituted nephrotoxic analogues, 2-chloroethanamine (CEA), 2-fluoroethanamine (FEA), and 1-phenyl-2-iodoethanamine (PIEA). The primary 1H NMR-detectable transformation during a 24 h incubation of confluent Madin Darby canine kidney (MDCK) cells with BEA, CEA, and FEA (at concentrations up to the IC50 determined by neutral red uptake) was the appearance in cell culture media of 2-oxazolidone (OX). Additional novel signals assigned as FEA carbamate (N-carbamoyl-2-fluoroethanamine) were observed in media collected following incubation of cells with FEA. We propose that N-carbamate intermediates are formed from the spontaneous reaction of these haloalkylamines with HCO3_-buffered growth media and that OX is formed from the carbamate via elimination of the hydrogen halide. Further 1H NMR experiments, conducted for up to 8 h at 25 °C on 5 mM solutions of BEA, CEA, and FEA in 2H2O containing a 20-fold excess of HCO3- at pH 7.6, demonstrated a time-dependent decrease in the concentration of the free haloalkylamines accompanied by the production of N-carbamate intermediates and OX. Under these pseudo-first-order reaction conditions, the formation of OX from BEA was complete within approximately 6 h. In similar reaction conditions OX formation from CEA (24 h after initiation) had reached 54% of its final equilibrium concentration. Equivalent experiments demonstrated that PIEA was almost completely converted to 4-phenyl-2-oxazolidinone (PHOX) within 2 h. These observations reveal the strong disposition of this series of haloalkylamines toward reaction with HCO3- and indicate that the compounds in this family may exist only transiently as free amines in vivo, where there will virtually always be excess HCO3-. The physiological relevance of the in vitro findings is further indicated by the NMR-detectable

Journal article

Nurok D, Hajdu P, Ellsworth B, Myers SS, Brogan TM, Lipkowitz KB, Kleyle RM, Glen RCet al., 1995, Solvent-Dependent Regression Equations for the Prediction of Retention in Planar Chromatography, Analytical Chemistry, Vol: 67, Pages: 4423-4430, ISSN: 0003-2700

Both first-and second-order regression models are presented that relate retention, as the Rf of individual solutes, the log k' of individual solutes, or the average Rf of a mixture of solutes, to the properties of the weak solvent in each of a series of 25 binary mobile phases consisting of a specified concentration of ethyl acetate as a common strong solvent The stepwise procedure is used for constructing these models, which are for either simulated or experimental separations on silica gel. Similar regression models are used to predict separation quality, defined by a suitable metric. A comparison of the forward and backward stepwise procedures finds that the former is the more reliable method for constructing these models. The solutes are either steroids or the p-nitrobenzyl esters of dansyl amino acids, and the solvent descriptors are density, dipole moment, molar volume, polarizability, saturated surface area, and unsaturated surface area. The quality of regression fits obtained with models using computed dipole moment is comparable to that obtained with models using experimental (literature) dipole moment Both nonstandardized and standardized regression models are presented. The relative contribution of each descriptor to the variability in retention may be estimated from the latter models. A set of three descriptors-dipole moment, polarizability, and saturated surface area-predicts Rf for each of the amino acid derivatives at an ethyl acetate mole fraction of 0.30. A set of two descriptors-dipole moment and saturated surface area-predicts log k' for each of these compounds at an ethyl acetate mole fraction of 0.20. Such concordance in descriptors is not found in models predicting retention of individual steroids. © 1995, American Chemical Society. All rights reserved.

Journal article

Beck B, Clark T, Glen RC, 1995, A detailed study of VESPA electrostatic potential-derived atomic charges, JOURNAL OF MOLECULAR MODELING, Vol: 1, Pages: 176-187, ISSN: 0948-5023

Journal article

Lindon JC, Nicholson JK, Wilson ID, 1995, The development and application of coupled HPLC-NMR spectroscopy, Advances in Chromatography, Pages: 315-382

Book chapter

ANTHONY ML, BEDDELL CR, LINDON JC, NICHOLSON JKet al., 1994, STUDIES ON THE COMPARATIVE TOXICITY OF S-(1,2-DICHLOROVINYL)-L-CYSTEINE, S-(1,2-DICHLOROVINYL)-L-HOMOCYSTEINE AND 1,1,2-TRICHLORO-3,3,3-TRIFLUORO-1-PROPENE IN THE FISCHER-344 RAT, ARCHIVES OF TOXICOLOGY, Vol: 69, Pages: 99-110, ISSN: 0340-5761

Journal article

SPRAUL M, HOFMANN M, LINDON JC, FARRANT RD, SEDDON MJ, NICHOLSON JK, WILSON IDet al., 1994, EVALUATION OF LIQUID-CHROMATOGRAPHY COUPLED WITH HIGH-FIELD H-1-NMR SPECTROSCOPY FOR DRUG METABOLITE DETECTION AND CHARACTERIZATION - THE IDENTIFICATION OF PARACETAMOL METABOLITES IN URINE AND BILE, NMR IN BIOMEDICINE, Vol: 7, Pages: 295-303, ISSN: 0952-3480

Journal article

SPRAUL M, NEIDIG P, KLAUCK U, KESSLER P, HOLMES E, NICHOLSON JK, SWEATMAN BC, SALMAN SR, FARRANT RD, RAHR E, BEDDELL CR, LINDON JCet al., 1994, AUTOMATIC REDUCTION OF NMR SPECTROSCOPIC DATA FOR STATISTICAL AND PATTERN-RECOGNITION CLASSIFICATION OF SAMPLES, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 12, Pages: 1215-1225, ISSN: 0731-7085

Journal article

AKIRA K, FARRANT RD, LINDON JC, CADDICK ST, NICHOLLS AW, NICHOLSON JKet al., 1994, HIGH-FIELD DEUTERIUM NUCLEAR-MAGNETIC-RESONANCE SPECTROSCOPIC MONITORING OF THE PHARMACOKINETICS OF SELECTIVELY DEUTERATED BENZOIC-ACID IN MAN, ANALYTICAL BIOCHEMISTRY, Vol: 221, Pages: 297-302, ISSN: 0003-2697

Journal article

FOXALL PJD, HARTLEY J, SINGER JM, SOUHAMI RL, NEILD GH, NICHOLSON JKet al., 1994, NMR MONITORING OF IFOSFAMIDE-INDUCED RENAL CORTICAL AND MEDULLARY INJURY, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 5, Pages: 392-392, ISSN: 1046-6673

Journal article

GLEN RC, 1994, A FAST EMPIRICAL-METHOD FOR THE CALCULATION OF MOLECULAR POLARIZABILITY, JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, Vol: 8, Pages: 457-466, ISSN: 0920-654X

Journal article

FARRANT RD, LINDON JC, NICHOLSON JK, 1994, INTERNAL TEMPERATURE CALIBRATION FOR H-1-NMR SPECTROSCOPY STUDIES OF BLOOD-PLASMA AND OTHER BIOFLUIDS, NMR IN BIOMEDICINE, Vol: 7, Pages: 243-247, ISSN: 0952-3480

Journal article

HOLMES E, FOXALL PJD, NICHOLSON JK, NEILD GH, BROWN SM, BEDDELL CR, SWEATMAN BC, RAHR E, LINDON JC, SPRAUL M, NEIDIG Pet al., 1994, AUTOMATIC DATA REDUCTION AND PATTERN-RECOGNITION METHODS FOR ANALYSIS OF H-1 NUCLEAR-MAGNETIC-RESONANCE SPECTRA OF HUMAN URINE FROM NORMAL AND PATHOLOGICAL STATES, ANALYTICAL BIOCHEMISTRY, Vol: 220, Pages: 284-296, ISSN: 0003-2697

Journal article

Elliott P, 1994, Nutritional factors in blood pressure., Pages: 595-601, ISSN: 0950-9240

High sodium intake, low potassium intake, high body mass index and high alcohol intake are established risk factors for high blood pressure (BP) in populations. For sodium, an overview of randomised controlled trials gave the estimate that reduction in sodium of around 70 mmol per day lowered BP on average by 2.9 mmHg systolic and 1.6 mmHg diastolic. An overview of within-population epidemiological studies (excluding INTERSALT), with correction for regression dilution, gave a pooled (simple) regression estimate that 100 mmol lower sodium was associated with BP lower by 4.5 mmHg systolic and 2.5 mmHg diastolic. In INTERSALT, across centres, average sodium excretion was significantly related to slope of BP with age, such that 100 mmol lower sodium was associated with 10 mmHg lower rise in SBP over 30 years; among individuals, previous estimates of the size of relationships of sodium and potassium to BP in INTERSALT were too low because of insufficient correction for the 'regression dilution' problem. For sodium, revised corrected regression estimates, with adjustment for age and sex, were 4.3 mmHg/100 mmol for SBP and 1.8 mmHg/100 mmol for DBP. After adjustment for other confounders, the corrected SBP-sodium regression estimate was 3.1 mmHg/100 mmol; it was 6.0 mmHg/100 mmol if body mass index was excluded from the regression model. The revised multiply adjusted regression estimate for SBP and potassium was -0.67 mmHg/10 mmol. Body mass index was positively related to BP in INTERSALT, consistent with other studies; on average, regression coefficients indicated 3.0 mmHg lower SBP and 2.2 mmHg lower DBP, for body weight lower by 10 kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Conference paper

ANTHONY ML, SWEATMAN BC, BEDDELL CR, LINDON JC, NICHOLSON JKet al., 1994, PATTERN-RECOGNITION CLASSIFICATION OF THE SITE OF NEPHROTOXICITY BASED ON METABOLIC DATA DERIVED FROM PROTON NUCLEAR-MAGNETIC-RESONANCE SPECTRA OF URINE, MOLECULAR PHARMACOLOGY, Vol: 46, Pages: 199-211, ISSN: 0026-895X

Journal article

SANDERSON PN, GLEN RC, PAYNE AWR, HUDSON BD, HEIDE C, TRANTER GE, DOYLE PM, HARRIS CJet al., 1994, CHARACTERIZATION OF THE SOLUTION CONFORMATION OF A CYCLIC RGD PEPTIDE ANALOG BY NMR-SPECTROSCOPY ALLIED WITH A GENETIC ALGORITHM APPROACH AND CONSTRAINED MOLECULAR-DYNAMICS, INTERNATIONAL JOURNAL OF PEPTIDE AND PROTEIN RESEARCH, Vol: 43, Pages: 588-596, ISSN: 0367-8377

Journal article

SPRAUL M, NICHOLSON JK, LYNCH MJ, LINDON JCet al., 1994, APPLICATION OF THE ONE-DIMENSIONAL TOCSY PULSE SEQUENCE IN 750 MHZ H-1-NMR SPECTROSCOPY FOR ASSIGNMENT OF ENDOGENOUS METABOLITE RESONANCES IN BIOFLUIDS, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 12, Pages: 613-618, ISSN: 0731-7085

Journal article

SEDDON MJ, SPRAUL M, WILSON ID, NICHOLSON JK, LINDON JCet al., 1994, IMPROVEMENT IN THE CHARACTERIZATION OF MINOR DRUG METABOLITES FROM HPLC-NMR STUDIES THROUGH THE USE OF QUANTIFIED MAXIMUM-ENTROPY PROCESSING OF NMR-SPECTRA, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 12, Pages: 419-424, ISSN: 0731-7085

Journal article

Elliott P, Stamler J, Stamler R, Dyer Aet al., 1994, Dietary salt and blood pressure., Lancet, Vol: 343, ISSN: 0140-6736

Journal article

Mervaala E, Karppanen H, 1994, Dietary salt and blood pressure., Lancet, Vol: 343, Pages: 545-546, ISSN: 0140-6736

Journal article

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