Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1‐cyano‐2‐hydroxy‐3‐butene in the rat

Abstract

The time-related metabolic effects of 1-cyano-2-hydroxy-3-butene (CHB, crambene), a naturally occurring nitrile and experimental model toxin causing exocrine pancreatitis, have been investigated in rats using high-resolution NMR spectroscopy of urine and serum in combination with pattern recognition analysis. Rats were administered CHB subcutaneously in two doses, 15 mg/kg dose (n = 10) and 150 mg/kg (n = 10), and conventional histopathology and clinical chemistry assessments were performed. Urine samples were collected at - 16 and 0, 8, 24, 48, 72, 96, 120, 144 and 168 h postdosing and serum samples were collected at 48 and 168 h postdosing; these were analyzed using a range of 1D and 2D NMR spectroscopic methods. The metabolic profile perturbations seen throughout the time-course of the study are described, and the application of the spectral correlation technique Statistical TOtal Correlation SpectroscopY (STOCSY) to detect both structural and novel toxicological connectivities between xenobiotic and endogenous metabolite signals is illustrated for the first time. As a result, it is suggested that the STOCSY approach may be of wider application in the identification of toxic versus nontoxic metabolites in drug metabolism studies.

Earthworm Sublethal Responses to Titanium Dioxide Nanomaterial in Soil Detected by 1H NMR Metabolomics

“…The area in the range δ = 4.70–4.85 ppm was excluded to eliminate small residual H 2 O/HOD signals, resulting in a total of 956 buckets for each earthworm. The data were normalized using probabilistic quotient normalization (PQN) to correct for differences in the total NMR signal measured for each sample which can vary with factors such as the mass of tissue extracted. ,− …”

Highly routinely reproducible alignment of 1H NMR spectral peaks of metabolites in huge sets of urines

“…In this case, interpretation of the O-PLS loadings are rather difficult due to peak distortions and the predictivity of the full resolution O-PLS model may be decreased when compared, in terms of the cross validation parameter Q 2 , to that of the data-reduced O-PLS one [16]. For this reason, it should be always convenient to try to align spectra prior to O-PLS modeling of full resolution spectral data [17]. In this respect the here proposed low pH alignment could helpfully cope with O-PLS approach.…”

CHAPTER 3. High‐Resolution NMR‐Based Metabolic Profiling in Drug Discovery and Development

“…STOCSY was applied to detect both structural and novel toxicological connectivities between xenobiotic and endogenous metabolite signals. 91 For example, CHB was found at high levels in the urine of high-dose animals at 8 h and interestingly the level was positively correlated to that of urinary glucose, suggesting that the compound was affecting the endocrine pancreas. In addition, the N-acetylcysteine conjugate was present in the urine of high-dose animals at 8 and 24 h, and its levels at 8 h were anti-correlated to glucose excretion.…”