Hepatotoxin-induced hypertaurinuria: a proton NMR study

Abstract

The urinary excretion of taurine by rats after dosing with various hepatotoxins has been investigated by 1H NMR spectroscopy. After single hepatotoxic doses of hydrazine, carbon tetrachloride, 1-naphthylisothiocyanate, or thioacetamide there was biochemical and histopathological evidence of hepatic damage. Proton NMR spectroscopy of the urine collected for 24 h after dosing from these animals revealed a marked elevation in taurine (control 11.9 mumole/h/kg) after dosing with thioacetamide (42.2 mumole/h/kg), carbon tetrachloride (52.5 mumole/h/kg), 1-naphthyl-isothiocyanate (80.4 mumole/h/kg) and hydrazine (52.9 mumole/h/kg). After allyl alcohol administration there was no increase in taurine excretion (7.5 mumol/h/kg). The excretion of taurine after hydrazine administration was dose related. High resolution proton NMR spectroscopic analysis of urine also revealed resonances from several metabolites of hydrazine, an N-acetylcysteine conjugate of allyl alcohol, and acetamide as a metabolite of thioacetamide after dosing with the respective compounds. Changes in endogenous substances that may be related to the pathological events were also detected, such as a decrease in the excretion of 2-oxoglutarate and citrate after both hydrazine and carbon tetrachloride administration. The results confirm that proton NMR spectroscopic analysis of urine is a powerful analytical tool for the evaluation and study of toxic substances. Furthermore, measurement of urinary taurine may provide a non-invasive indicator of acute hepatic damage with certain classes of hepatotoxins.

Investigations into Biochemical Changes Due to Diurnal Variation and Estrus Cycle in Female Rats Using High-Resolution 1H NMR Spectroscopy of Urine and Pattern Recognition

“…An increase in the level of the ␤-amino acid taurine was observed in urines collected overnight, compared with daytime urine samples. As we have previously proposed, taurinuria is as a biomarker for liver injury (26); therefore this observation is important as it could confound toxicological assessments utilizing taurine measurements if the effects of diurnal variation are not considered.…”

NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition

“…25,26 1 H NMR spectroscopy has been successfully used to identify a number of novel metabolic markers of organ-specific toxicity in the rat. 12,13,[27][28][29] Currently, the role of metabonomics in toxicology is being evaluated by the COMET (the Consortium on Metabonomic Toxicology) project, 3 which has generated databases and predictive expert systems based on a wide range of model toxins, using 1 H NMR spectroscopy and chemometric analysis of rodent urine and serum. 30,31 NMR-based metabonomics has proven to be diagnostic in determining organ of effect after administration of toxic compounds, with different toxins giving different patterns in the NMR spectra, even those damaging the same organ, such as nephrotoxins.…”

“…32 Elevations in the levels of urinary taurine have also been associated with liver dysfunction. 27,33 However, many endogenous metabolites, such as taurine, fluctuate in concentration as a result of normal physiological variation. 5 Therefore, its significance is measured by concomitant changes in other metabolites, for instance, elevated creatine 34,35 or a decrease in hippurate.…”

“…5 Therefore, its significance is measured by concomitant changes in other metabolites, for instance, elevated creatine 34,35 or a decrease in hippurate. 27,33 The combined increases in taurine and creatine concentrations have been associated with reduced liver function after treatment of rats with carbon tetrachloride, thioacetamide and allyl alcohol. 27,34 In contrast, reductions in TCA cycle intermediates are believed to be non-specific biochemical changes, due in part to a general perturbation in energy metabolism and reduced food intake, rather than relating to tissue-specific toxicity.…”

“…27,33 The combined increases in taurine and creatine concentrations have been associated with reduced liver function after treatment of rats with carbon tetrachloride, thioacetamide and allyl alcohol. 27,34 In contrast, reductions in TCA cycle intermediates are believed to be non-specific biochemical changes, due in part to a general perturbation in energy metabolism and reduced food intake, rather than relating to tissue-specific toxicity. Therefore, there is a wealth of information available in the 1D NMR spectrum of a biofluid sample which can be related to organ toxicity.…”