Development of a multivariate statistical model to predict peroxisome proliferation in the rat, based on urinary 1H-NMR spectral patterns.
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.
Connor
Susan C
SC
Safety Assessment, GlaxoSmithKline, Park Road, Ware, Hertfordshire, Herts SG12 0DP, UK. susan.c.connor@gsk.com
Hodson
Mark P
MP
Ringeissen
Stephanie
S
Sweatman
Brian C
BC
McGill
Paul J
PJ
Waterfield
Catherine J
CJ
Haselden
John N
JN
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002262:Carboxy-Lyases / Q000096:biosynthesis; D015536:Down-Regulation; D011345:Fenofibrate / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015233:Models, Statistical; D015999:Multivariate Analysis; D009929:Organ Size / Q000187:drug effects; D010430:Pentosyltransferases / Q000096:biosynthesis; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D020025:Peroxisome Proliferators / Q000378:metabolism / Q000633:toxicity*; D020675:Peroxisomes / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015854:Up-Regulation; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
D047492:Peroxisome Proliferator-Activated Receptors; D020025:Peroxisome Proliferators; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D011345:Fenofibrate