Tryptophan-NAD super(+) pathway metabolites as putative biomarkers and predictors of peroxisome proliferation

• Published in: Archives of toxicology 2005-04, Vol.79 (4), p.208-223
• Main Authors: Delaney, Jane, Hodson, Mark P, Thakkar, Hansa, Connor, Susan C, Sweatman, Brian C, Kenny, Steve P, McGill, Paul J, Holder, Julie C, Hutton, Kathryn A, Haselden, John N, Waterfield, Catherine J
• Format: Article
• Language: English
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-004-0625-5

The present study was designed to provide further information about the relevance of raised urinary levels of N-methylnicotinamide (NMN), and/or its metabolites N-methyl-4-pyridone-3-carboxamide (4PY) and N-methyl-2-pyridone-3-carboxamide (2PY), to peroxisome proliferation by dosing rats with known peroxisome proliferator-activated receptor alpha (PPAR alpha ) ligands [fenofibrate, diethylhexylphthalate (DEHP) and long-chain fatty acids (LCFA)] and other compounds believed to modulate lipid metabolism via PPAR alpha -independent mechanisms (simvastatin, hydrazine and chlorpromazine). Urinary NMN was correlated with standard markers of peroxisome proliferation and serum lipid parameters with the aim of establishing whether urinary NMN could be used as a biomarker for peroxisome proliferation in the rat. Data from this study were also used to validate a previously constructed multivariate statistical model of peroxisome proliferation (PP) in the rat. The predictive model, based on super(1)H nuclear magnetic resonance (NMR) spectroscopy of urine, uses spectral patterns of NMN, 4PY and other endogenous metabolites to predict hepatocellular peroxisome count. Each treatment induced pharmacological (serum lipid) effects characteristic of their class, but only fenofibrate, DEHP and simvastatin increased peroxisome number and raised urinary NMN, 2PY and 4PY, with simvastatin having only a transient effect on the latter. These compounds also reduced mRNA expression for aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase, EC 4.1.1.45), the enzyme believed to be involved in modulating the flux of tryptophan through this pathway, with decreasing order of potency, fenofibrate (-10.39-fold) >DEHP (-3.09-fold) >simvastatin (-1.84-fold). Of the other treatments, only LCFA influenced mRNA expression of ACMSDase (-3.62-fold reduction) and quinolinate phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) (-2.42-fold) without any change in urinary NMN excretion. Although there were no correlations between urinary NMN concentration and serum lipid parameters, NMN did correlate with peroxisome count (r super(2)=0.63) and acyl-CoA oxidase activity (r super(2)=0.61). These correlations were biased by the large response to fenofibrate compared to the other treatments; nevertheless the data do indicate a relationship between the tryptophan-NAD super(+) pathway and PPAR alpha -dependent pathways, making this metabolite a potentially useful biomarker to detect PP. In order to streng