Development of a multivariate statistical model to predict peroxisome proliferation in the rat, based on urinary ¹H-NMR spectral patterns

Abstract

A previous report of this work (Ringeissen et al. 2003) described the use of nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical data analysis (MVDA) to identify novel biomarkers of peroxisome proliferation (PP) in Wistar Han rats. Two potential biomarkers of peroxisome proliferation in the rat were described, N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY). The inference from these results was that the tryptophan-nicotinamide adenine dinucleotide (NAD⁺) pathway was altered in correlation with peroxisome proliferation, a hypothesis subsequently confirmed by TaqMan® analysis of the relevant genes encoding two key enzymes in the pathway, aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) and quinolinate phosphoribosyltransferase (EC 2.4.2.19). The objective of the present study was to investigate these data further and identify other metabolites in the NMR spectrum correlating equally with PP. MVDA Partial Least Squares (PLS) models were constructed that provided a better prediction of PP in Wistar Han rats than levels of 4PY and NMN alone. The resulting Wistar Han rat predictive models were then used to predict PP in a test group of Sprague Dawley rats following administration of fenofibrate. The models predicted the presence or absence of PP (above on arbitrary threshold of >2-fold mean control) in all Sprague Dawley rats in the test group.

Keywords: :

• proton nuclear magnetic resonance spectroscopy
• multivariate statistical data analysis
• peroxisome proliferation
• rat
• tryptophan-nicotinamide adenine dinucleotide pathway
• partial least squares
• prediction
• threshold
• peroxisome proliferator-activated receptor
• metabolic profile
• metabonomics
• metabolomics

Nomenclature: NMR, Nuclear magnetic resonance;; MVDA, Multivariate statistical data analysis;; PP, Peroxisome proliferation;; NMN, N-methylnicotinamide;; 4PY, N-methyl-4-pyridone-3-carboxamide;; NAD⁺, Nicotinamide adenine dinucleotide;; ACMSD, Aminocarboxymuconate-semialdehyde decarboxylase;; QAPRT, Quinolinate phosphoribosyltransferase;; PLS, Partial least squares or projection to latent structures;; PPAR, Peroxisome proliferator-activated receptors;; TEM, Transmission electron microscopy;; RLW, Relative liver weight;; Pxc, Peroxisome count;; HPLC, High performance liquid chromatography;; WH, Wistar han;; SD, Sprague Dawley;; LC, Liquid chromatography;; AST, Aspartate aminotransferase;; ALT, Alanine aminotransferase;; ALP, Alkaline phosphatase;; CHL, Cholesterol;; Gluc, Glucose;; Tprot, Total protein;; Alb, Albumin;; HDL, High density lipoprotein;; LDL, Low density lipoprotein;; VLDL, Very low density lipoprotein;; TRG, Triglycerides;; NOESY, Nuclear overhauser enhancement spectroscopy;; RD, Relaxation delay;; FID, Free induction decay;; TSP, Sodium 3-trimethylsilyl-[2,2,3,3-²H₄]-1-propionate;; PCA, Principal component analysis;; PLS-DA, Partial least squares-discriminant analysis;; LC/MS, Liquid chromatography/mass spectrometry;; LD, Low dose;; HD, High dose;; TCA, Tricarboxylic acid cycle;; PC, Principal component;; UV, Unit variance scaling;

Nomenclature: NMR, Nuclear magnetic resonance;; MVDA, Multivariate statistical data analysis;; PP, Peroxisome proliferation;; NMN, N-methylnicotinamide;; 4PY, N-methyl-4-pyridone-3-carboxamide;; NAD⁺, Nicotinamide adenine dinucleotide;; ACMSD, Aminocarboxymuconate-semialdehyde decarboxylase;; QAPRT, Quinolinate phosphoribosyltransferase;; PLS, Partial least squares or projection to latent structures;; PPAR, Peroxisome proliferator-activated receptors;; TEM, Transmission electron microscopy;; RLW, Relative liver weight;; Pxc, Peroxisome count;; HPLC, High performance liquid chromatography;; WH, Wistar han;; SD, Sprague Dawley;; LC, Liquid chromatography;; AST, Aspartate aminotransferase;; ALT, Alanine aminotransferase;; ALP, Alkaline phosphatase;; CHL, Cholesterol;; Gluc, Glucose;; Tprot, Total protein;; Alb, Albumin;; HDL, High density lipoprotein;; LDL, Low density lipoprotein;; VLDL, Very low density lipoprotein;; TRG, Triglycerides;; NOESY, Nuclear overhauser enhancement spectroscopy;; RD, Relaxation delay;; FID, Free induction decay;; TSP, Sodium 3-trimethylsilyl-[2,2,3,3-²H₄]-1-propionate;; PCA, Principal component analysis;; PLS-DA, Partial least squares-discriminant analysis;; LC/MS, Liquid chromatography/mass spectrometry;; LD, Low dose;; HD, High dose;; TCA, Tricarboxylic acid cycle;; PC, Principal component;; UV, Unit variance scaling;