Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography.
This study identified two potential novel biomarkers of peroxisome proliferation in the rat. Three peroxisome proliferator-activated receptor (PPAR) ligands, chosen for their high selectivity towards the PPARalpha, -delta and -gamma subtypes, were given to rats twice daily for 7 days at doses known to cause a pharmacological effect or peroxisome proliferation. Fenofibrate was used as a positive control. Daily treatment with the PPARalpha and -delta agonists produced peroxisome proliferation and liver hypertrophy. 1H nuclear magnetic resonance spectroscopy and multivariate statistical data analysis of urinary spectra from animals given the PPARalpha and -delta agonists identified two new potential biomarkers of peroxisome proliferation--N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY)--both endproducts of the tryptophan-nicotinamide adenine dinucleotide (NAD+) pathway. After 7 days, excretion of NMN and 4PY increased 24- and three-fold, respectively, following high doses of fenofibrate. The correlation between total NMN excretion over 7 days and the peroxisome count was r=0.87 (r2=0.76). Plasma NMN, measured using a sensitive high performance liquid chromatography method, was increased up to 61-fold after 7 days' treatment with high doses of fenofibrate. Hepatic gene expression of aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) was downregulated following treatment with the PPARalpha and -delta agonists. The decrease was up to 11-fold compared with controls in the groups treated with high doses of fenofibrate. This supports the link between increased NMN and 4PY excretion and regulation of the tryptophan-NAD+ pathway in the liver. In conclusion, NMN, and possibly other metabolites in the pathway, are potential non-invasive surrogate biomarkers of peroxisome proliferation in the rat.
Ringeissen
Stephanie
S
Safety Assessment, GlaxoSmithKline, Park Road, Ware, Herts, SG12 ODP, UK.
Connor
Susan C
SC
Brown
H Roger
HR
Sweatman
Brian C
BC
Hodson
Mark P
MP
Kenny
Steve P
SP
Haworth
Richard I
RI
McGill
Paul
P
Price
Mark A
MA
Aylott
Mike C
MC
Nunez
Derek J
DJ
Haselden
John N
JN
Waterfield
Catherine J
CJ
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002262:Carboxy-Lyases / Q000096:biosynthesis; D002851:Chromatography, High Pressure Liquid; D008024:Ligands; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D020025:Peroxisome Proliferators / Q000032:analysis* / Q000378:metabolism / Q000494:pharmacology; D020675:Peroxisomes / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D014157:Transcription Factors / Q000819:agonists
D015415:Biomarkers; D008024:Ligands; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D009536:Niacinamide; C016590:N(1)-methyl-4-pyridone-5-carboxamide; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; C024058:N(1)-methylnicotinamide