Metabonomic Deconvolution Of Embedded Toxicity: Application To Thioacetamide Hepato- and Nephrotoxicity

详细信息    查看全文

• 作者：Nigel J. Waters ; Catherine J. Waterfield ; R. Duncan Farrant ; Elaine Holmes ; and Jeremy K. Nicholson
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：April 2005
• 年：2005
• 卷：18
• 期：4
• 页码：639 - 654
• 全文大小：560K
• 年卷期：v.18,no.4(April 2005)
• ISSN：1520-5010

文摘

We present here the potential of an integrated metabonomic strategy to deconvolute thebiofluid metabolic signatures in experimental animals following multiple organ toxicities, usingthe well-known hepato- and nephrotoxin, thioacetamide. Male Han-Wistar rats were dosedwith thioacetamide (150 mg/kg, n = 25), and urine, plasma, liver, and kidney samples werecollected postdose for conventional NMR and magic angle spinning (MAS) NMR spectroscopy.These data were correlated with histopathology and plasma clinical chemistry collected at alltime points. ¹H MAS NMR data from liver and kidney were related to sequential ¹H NMRmeasurements in urine and plasma using pattern recognition methods. One-dimensional ¹HNMR spectra were data-reduced and analyzed using principal components analysis (PCA) toshow the time-dependent biochemical variations induced by thioacetamide toxicity. From theeigenvector loadings of the PCA, those regions of the ¹H NMR spectra, and hence thecombinations of endogenous metabolites marking the main phase of the toxic episode, wereidentified. The thioacetamide-induced biochemical manifestations included a renal and hepaticlipidosis accompanied by hypolipidaemia; increased urinary excretion of taurine and creatineconcomitant with elevated creatine in liver, kidney, and plasma; a shift in energy metabolismcharacterized by depleted liver glucose and glycogen; reduced urinary excretion of tricarboxylicacid cycle intermediates and raised plasma ketone bodies; increased levels of tissue and plasmaamino acids leading to amino aciduria verifying necrosis-enhanced protein degradation andrenal dysfunction; and elevated hepatic and urinary bile acids indicating secondary damageto the biliary system. This integrated metabonomic approach has been able to identify thetissue of origin for biomarkers present in the metabolic profiles of biofluids, following the onsetand progression of a multiorgan pathology, and as such highlights its potential in the evaluationof embedded toxicity in novel drug candidates.