title: Heteronuclear 1H-31P statistical total correlation NMR spectroscopy of intact liver for metabolic biomarker assignment: application to galactosamine-induced hepatotoxicity.
abstract: As part of our ongoing development of methods for enhanced biomarker information recovery from spectroscopic data we present the first example of a new hetero-nuclear statistical total correlation spectroscopy (HET-STOCSY) approach applied to intact tissue samples collected as part of a toxicological study. One-dimensional 1H and 31P-{1H} magic angle spinning (MAS) NMR spectra of intact liver samples after galactosamine (galN) treatment to rats and after cotreatment of galN plus uridine were collected at 275 K. Individual samples were also followed by 1H and 31P-{1H} MAS NMR through time generating time dependent modulations in metabolite signatures relating to toxicity. High-resolution 1H NMR spectra of urine and plasma and clinical chemical data were also collected to establish a biological framework in which to place these novel statistical heterospectroscopic data. In HET-STOCSY, calculation of the covariance between the 31P-{1H} and 1H NMR signals of phosphorus containing metabolites allows their molecular connectivities to be established and the construction of virtual two-dimensional heteronuclear correlation spectra that connect all protons on the molecule to the heteroatom. We show how HET-STOCSY applied to MAS NMR spectra of liver samples can be used to augment biomarker detection. This approach is generic and can be applied to correlate the covarying signals for any spin-active nuclei where there is parallel or serial collection of data.
authors.affiliation: Department of Biomolecular Medicine, Sir Alexander Fleming Building, SORA Division, Faculty of Medicine, Imperial College London, SW7 2AZ, U.K.
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
authors.forename: Young-Shick
authors.initials: YS
authors.lastname: Hong
authors.forename: Olivier
authors.initials: O
authors.lastname: Cloarec
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Rhode
authors.forename: Michael D
authors.initials: MD
authors.lastname: Reily
authors.forename: Donald G
authors.initials: DG
authors.lastname: Robertson
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism* / Q000652:urine; D005688:Galactosamine / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D010759:Phosphorus Isotopes; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D010759:Phosphorus Isotopes; D011522:Protons; D005688:Galactosamine