Chemometric Models for Toxicity Classification Based on NMR Spectra of Biofluids
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- 作者：Elaine Holmes ; Andrew W. Nicholls ; John C. Lindon ; Susan C. Connor ; John C. Connelly ; John N. Haselden ; Stephen J. P. Damment ; Manfred Spraul ; Peter Neidig ; and Jeremy K. Nicholson
- 刊名：Chemical Research in Toxicology
- 出版年：2000
- 出版时间：June 2000
- 年：2000
- 卷：13
- 期：6
- 页码：471 - 478
- 全文大小：109K
- 年卷期：v.13,no.6(June 2000)
- ISSN：1520-5010
文摘
1H NMR spectroscopic and pattern recognition (PR)-based methods were used to investigatethe biochemical variability in urine obtained from control rats and from rats treated with ahydrazine (a model hepatotoxin) or HgCl2 (a model renal cortical toxin). The 600 MHz 1H NMRspectra of urine samples obtained from vehicle- or toxin-treated Han-Wistar (HW) and Sprague-Dawley (SD) rats were acquired, and principal components analysis (PCA) and soft independentmodeling of class analogy (SIMCA) analysis were used to investigate the 1H NMR spectraldata. Variation and strain differences in the biochemical composition of control urine sampleswere assessed. Control urine 1H NMR spectra obtained from the two rat strains appearedvisually similar. However, chemometric analysis of the control urine spectra indicated thatHW rat urine contained relatively higher concentrations of lactate, acetate, and taurine andlower concentrations of hippurate than SD rat urine. Having established the extent ofbiochemical variation in the two populations of control rats, PCA was used to evaluate themetabolic effects of hydrazine and HgCl2 toxicity. Urinary biomarkers of each class of toxicitywere elucidated from the PC loadings and included organic acids, amino acids, and sugars inthe case of mercury, while levels of taurine, 
-alanine, creatine, and 2-aminoadipate wereelevated after hydrazine treatment. SIMCA analysis of the data was used to build predictivemodels (from a training set of 416 samples) for the classification of toxicity type and strain ofrat, and the models were tested using an independent set of urine samples (n = 124). Usingmodels constructed from the first three PCs, 98% of the test samples were correctly classifiedas originating from control, hydrazine-treated, or HgCl2-treated rats. Furthermore, this methodwas sensitive enough to predict the correct strain of the control samples for 79% of the data,based upon the class of best fit. Incorporation of these chemometric methods into automatedNMR-based metabonomics analysis will enable on-line toxicological assessment of biofluidsand will provide a tool for probing the mechanistic basis of organ toxicity.
-alanine, creatine, and 2-aminoadipate wereelevated after hydrazine treatment. SIMCA analysis of the data was used to build predictivemodels (from a training set of 416 samples) for the classification of toxicity type and strain ofrat, and the models were tested using an independent set of urine samples (n = 124). Usingmodels constructed from the first three PCs, 98% of the test samples were correctly classifiedas originating from control, hydrazine-treated, or HgCl2-treated rats. Furthermore, this methodwas sensitive enough to predict the correct strain of the control samples for 79% of the data,based upon the class of best fit. Incorporation of these chemometric methods into automatedNMR-based metabonomics analysis will enable on-line toxicological assessment of biofluidsand will provide a tool for probing the mechanistic basis of organ toxicity.