Potential urinary and plasma biomarkersof 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
Potential urinary and plasma biomarkersof 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
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DOI：
10.1080/1354750031000149124
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发表时间：
2003-05-01
期刊：
影响因子：
2.6
通讯作者：
Waterfield, CJ
中科院分区：
文献类型：
--
作者：
Ringeissen, S;Connor, SC;Waterfield, CJ
这项研究确定了两个潜在的新的生物标志物，在大鼠体内的过氧化物酶体增殖。三种过氧化物酶体增殖物激活受体(PPAR)配体，因其对PPARα、-β和-伽马亚型具有高度的选择性而被选中，每天给药两次，连续给药7天，剂量已知会导致药理效应或过氧化酶体增殖。非诺贝特作为阳性对照。每天使用PPARα和-Delta激动剂治疗会导致过氧化物酶体增殖和肝脏肥大。H-1核磁共振波谱和对给予PPARα和-Delta激动剂的动物尿谱的多元统计数据分析确定了两个新的潜在的过氧化物酶体增殖的生物标志物-N-甲基烟酰胺(NMN)和N-甲基-4-吡啶酮-3-甲酰胺(4PY)-这两个生物标志物都是色氨酸-烟酰胺腺嘌呤二核苷酸(NAD(+))途径的终产物。7天后，服用高剂量非诺贝特后，NMN和4PY的排泄量分别增加了24倍和3倍。7d内NMN总排泄量与过氧化物酶体数的相关系数r=0.87(r(2)=0.76)。高剂量非诺贝特治疗7天后，用灵敏的高效液相色谱法测定的血浆NMN增加了61倍。经PPARα和-Delta激动剂处理后，肝组织氨基羧酸半醛脱羧酶(EC 4.1.1.45)基因表达下调。在接受高剂量非诺贝特治疗的组中，与对照组相比，这一比例下降了11倍。这支持了NMN和4PY排泄增加与肝脏中色氨酸-NAD(+)途径调节之间的联系。总之，NMN，以及可能的其他代谢产物，可能是大鼠体内过氧化物酶体增殖的潜在的非侵入性替代生物标志物。
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. H-1 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 (r(2) = 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.