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J A Timbrell

Publications and source records attributed to J A Timbrell.

At least 55 records · Page 3Linked to original sources
PubMed1991

Taurine, a possible urinary marker of liver damage: a study of taurine excretion in carbon tetrachloride-treated rats.

Carbon tetrachloride (CCl4) caused a dose-dependent increase in urinary taurine which correlated with both the histological and biochemical assessment of liver damage. The peak elevation in urinary taurine occurred within the first 48 h after dosing but there was still significant taurinuria 72 and 96 h after the intermediate dose (1 ml.kg-1) and highest dose (2 ml.kg-1), respectively. Levels of taurine in serum were also elevated over the 24 h period following a hepatotoxic dose (2 ml.kg-1) of CCl4. In contrast, although initially elevated, levels of taurine in the liver declined over the 24 h period following dosing and were significantly lower 96 h after a hepatotoxic dose of CCl4 (2 ml.kg-1). Male rats showed a different urinary profile for taurine than female rats after dosing with CCl4. A reduction in food intake seemed to lower urinary taurine levels although these changes were not statistically significant. There was a significant correlation between the level of urinary taurine and the level of serum AST for individual animals given a hepatotoxic dose of CCl4 (2 ml.kg-1). The data presented suggest that: i) taurine is produced by the liver in response to a toxic insult and subsequent leakage from damaged cells leads to increased levels in the urine; ii) the urinary taurine level may be a useful non-invasive marker of liver damage.

Alanine Transaminase↗
PubMed1990

Course of ATP depletion in hydrazine hepatotoxicity.

The effect of hydrazine on ATP levels has been investigated in rats in vivo and in hepatocytes in vitro. Hydrazine was found to cause a dose-dependent depletion of hepatic ATP in vivo 3 h after dosing. In isolated hepatocytes in vitro hydrazine also caused a concentration-dependent depletion of ATP which preceded cytotoxicity as indicated by loss of cell viability. The ATP depletion in isolated hepatocytes was also significant at a concentration of hydrazine which was not cytotoxic. Attempts to determine hepatic ATP depletion in vivo over time using topical 31P NMR were confounded by the effects of the thiopentobarbitone used to anaesthetise the animals. This was found to ameliorate the effects of hydrazine on ATP depletion but potentiate the lethality of hydrazine. Consequently, although ATP depletion was detected in some hydrazine-treated animals, this was only observed in animals which subsequently died. The results indicate that ATP depletion may underlie the hepatotoxicity of hydrazine.

Adenosine Triphosphate↗
PubMed1990

Hepatotoxin-induced hypertaurinuria: a proton NMR study.

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.

1-Naphthylisothiocyanate↗
PubMed1990

Studies on the relationship between acute testicular damage and urinary and plasma creatine concentration.

A single dose of cadmium chloride (3.23 mumol Cd2+/kg) causing acute testicular damage in male rats also caused significant creatinuria and creatinaemia at 48 h after dosing. Doses of cadmium which did not cause testicular necrosis did not cause creatinuria or creatinaemia. Surgical ligation of the pampiniform plexus also caused ischaemic necrosis of the testis and this was followed by significant creatinuria and creatinaemia. However, neither orchidectomy followed by a toxic dose of cadmium, orchidectomy alone nor sham operation caused significant creatinuria or creatinaemia. Cadmium dosing induced a temporary loss of body weight which was less than that caused by food restriction. Food restriction did not cause significant creatinuria but did cause significant creatinaemia. These data suggest that the creatine is derived from the damaged testis and that measurement of urinary creatine may be a useful non-invasive means of detecting acute testicular damage caused by exposure to chemicals or mechanical impairment of blood flow.

Animals↗
PubMed1989

Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat.

The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and 1H-NMR spectroscopic methods. Dosing PAP (25-100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. 1H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, 1H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by 1H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by 1H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. 1H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.

Amino Acids↗
PubMed1989

Urinary creatine as a possible marker for testicular damage: studies with the testicular toxic compound 2-methoxyethanol.

A single dose of 500 mg/kg of 2-methoxyethanol given to male rats caused testicular damage, detected by histopathology, a significant reduction in relative testis weight, and a significant rise in urinary creatine, maximal at 48 h after dosing. Further studies showed that the reduction in relative testis weight and creatine excretion were dose related. Conversely, urinary creatinine showed a dose-related decrease at 24 h after dosing. In female rats dosed with 500 mg/kg of 2-methoxyethanol, there was no increase in urinary creatine or decrease in creatinine. These data suggest that urinary creatine may be a useful, noninvasive marker of testicular damage.

Animals↗
PubMed1989

Investigation of lipid peroxidation induced by hydrazine compounds in vivo in the rat.

Phenylhydrazine caused lipid peroxidation in rats in vivo as detected by expiration of ethane but this was not due to lipid peroxidation in liver, as there was no associated MDA production in this tissue. Hydrazine did not cause either ethane expiration or MDA formation. Both hydrazine and phenylhydrazine caused a significant increase in propane expiration. Phenylhydrazine significantly decreased packed cell volume and haemoglobin levels but hydrazine had no effect on these parameters. These data indicate that the early toxicity of hydrazine does not involve peroxidation of lipids whereas phenylhydrazine causes lipid peroxidation possibly within the erythrocyte, perhaps by interaction with red cell haemoglobin.

Alkanes↗
PubMed1989

Quantitative high resolution 1H NMR urinalysis studies on the biochemical effects of cadmium in the rat.

Quantitative changes in the urinary excretion patterns of low molecular weight compounds were followed for up to 30 days after dosing of adult Sprague-Dawley rats with single intraperitoneal injections of CdCl2 (6-24 mumol/kg), using high resolution 1H NMR multicomponent urinalysis. There was a marked reduction in the rate of urinary excretion of citrate, 2-oxoglutarate, and succinate within 4.5 hr of the administration of 24 mumol/kg Cd2+. This continued for up to 4 days after dosing in male rats and was consistent with a renal tubular acidosis, caused by inhibition of carbonic anhydrase. Histological examination of the kidneys showed no evidence of structural abnormalities at any Cd2+ dose level. Creatinine excretion was not affected by Cd2+ treatment at any dose level but hippurate excretion was significantly reduced. Severe testicular damage was noted within 24 hr of Cd2+ treatment at doses of greater than 9 mumol/kg and the degree of damage appeared to be correlated with the presence of large amounts of creatine (up to 20 mM) in the urine. Analysis of homogenates of healthy testicular material indicated the presence of high concentrations of free creatine. Cadmium-induced creatinuria appears to result from direct release of creatine from the necrotic cells of the seminiferous tubules and, hence, the measurement of creatine excretion rates may provide a useful noninvasive indicator of testicular necrosis. Because NMR is nonselective in terms of metabolite detection, this work has shed new light on the changes in urinary composition arising from Cd toxicity. As such, the technique is potentially very valuable in the search for new metabolic markers of toxicity and organ dysfunction.

Animals↗
PubMed1988

Metabolic profiling of body fluids by proton NMR: self-poisoning episodes with paracetamol (acetaminophen).

1H NMR spectra of urine and plasma from subjects who had taken paracetamol (acetaminophen) at a therapeutic dose or in self-poisoning episodes (both fatal and nonfatal) are compared. They provide convenient metabolic profiles. For overdose cases, intense resonances corresponding to high levels of both drug and endogenous metabolites are observed. The ratios of glucuronide to sulfate conjugates are unusually high in urine from overdose cases. Elevated levels of the cysteinyl and N-acetyl cysteinyl conjugates reflect increased glutathione conjugation in the liver. The observed excretion of high levels of amino acids by overdose subjects is suggestive of drug-induced hepatic damage. No resonances for drug metabolites are detected in plasma samples. However, characteristic and abnormally intense resonances for the amino acids Phe, Tyr, His, Gln, Pro, Ala, Val, Lys, Met, Ser, and Thr are indicative of severe liver failure and disruption of normal deamination and transamination processes.

Acetaminophen↗
PubMed1988

Comparative hepatotoxicity and metabolism of N-methylformamide in rats and mice.

N-methylformamide (NMF) produced dose-dependent zone 3 haemorrhagic necrosis in mice; the threshold dose was 100-200 mg/kg. In rats a dose of 1000 mg/kg caused hepatic damage in some animals and slight elevations of plasma transaminases. A species difference in susceptibility to NMF-induced hepatotoxicity is clearly indicated. NMF depleted liver non-protein sulphydryl (NPSH) in a dose-dependent manner in mice, but not in rats. Depletion of liver glutathione by buthionine sulphoximine or diethylmaleate potentiated the hepatotoxicity of NMF in mice. [14C]-methyl NMF was metabolised by mice and rats and a number of urinary metabolites including an N-acetylcysteine conjugate, methylamine and N-hydroxymethylformamide were detected. There were no qualitative differences in the metabolites between rats and mice but mice metabolised NMF much faster and more extensively than rats.

Animals↗
PubMed1985

Plasma hydrazine concentrations in man after isoniazid and hydralazine administration.

By using a specific sensitive stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) assay, hydrazine was detected in the plasma of eight healthy male volunteer subjects taking isoniazid (300 mg daily) for 2 weeks. Accumulation of hydrazine occurred in slow-acetylator phenotypes. Hydrazine was also detected in the plasma of eight out of 14 hypertensive patients treated chronically with hydralazine (200 mg daily). However, the concentrations of hydrazine observed were much lower than in the isoniazid study and were close to the limit of detection. As hydrazine is hepatotoxic, mutagenic and carcinogenic in animals, its presence in human plasma has important toxicological implications.

Acetylation↗
PubMed1985

A study of the effects of rifampicin on isoniazid metabolism in human volunteer subjects.

The effect of rifampicin on the metabolism of isoniazid in human volunteer subjects has been investigated. The urinary metabolites of isoniazid after a single dose and after six daily doses of isoniazid plus rifampicin were examined. The isoniazid-rifampicin combination clearly increased the ratio of urinary 6-beta-hydroxycortisol to 17-hydroxycorticosteroids, indicating that induction of the microsomal enzymes had occurred. However, no significant changes in the urinary metabolites of isoniazid were detected, and therefore it is not possible to predict the effect of rifampicin on isoniazid hepatotoxicity.

17-Hydroxycorticosteroids↗
PubMed1985

Proton NMR spectra of urine as indicators of renal damage. Mercury-induced nephrotoxicity in rats.

Rats were injected intraperitoneally with HgCl2 at doses of 2.5, 5, 7.5, and 10 mumol of Hg/kg. Urine was collected over a 24-hr period. At this time, plasma samples were taken and kidney damage was assessed by histological examination. Urinary gamma-glutamyltransferase levels were significantly elevated at Hg2+ doses of 7.5 and 10 mumol/kg, consistent with the detection of acute tubular necrosis by light microscopy. Resonances for a large number of low molecular weight metabolites were assigned in high resolution 1H NMR spectra of rat urine. Spectra from small volumes of urine (about 0.5 ml) were obtained in less than 5 min with no pretreatment. Significant Hg2+ dose-related decreases in the excretion of creatinine and citrate and increases of glucose, glycine, alanine, alpha-ketoglutarate, succinate, and acetate were detected. Elevated levels of lactate and creatinine in plasma of rats receiving the two highest doses were found by 1H NMR. There was a good correspondence between the histopathology, enzyme excretion, and 1H NMR urinary metabolite fingerprints in the assessment of Hg2+-induced renal damage. 1H NMR provided a sensitive measure of mercury-induced nephrotoxic lesions, and information on the molecular basis of mercury cytotoxicity was derived from the abnormal patterns of metabolite excretion. These suggested that primary metabolic effects of mercury were upon mitochondrial metabolism, in particular inhibition of certain citric acid cycle enzymes leading to decreased utilization of alpha-ketoglutarate and succinate by the renal tubular cells. The decrease in urinary citrate associated with Hg2+ dosing was attributed to intracellular, tubular acidosis with concomitant enhanced citrate reabsorption. The acidosis was assumed to arise from a combination of the inhibition of tubular carbonic anhydrase and a mild metabolic lactic acidosis due to increased activity of anaerobic pathways in the kidney. The possible extension of the 1H NMR techniques to the investigation of the nephrotoxic potential of other compounds and drugs is discussed.

Animals↗
PubMed1985

A high resolution proton nuclear magnetic resonance approach to the study of hepatocyte and drug metabolism. Application to acetaminophen.

1H spin echo NMR spectra of intact hepatocytes, isolated from rat liver, showed resonances for glucose, mobile fatty acids, and +N(CH3)3 groups including choline headgroups of phosphoglycerides. Spectra from extracts of the same cells contained many more well resolved resonances due to low Mr metabolites. These included signals for free amino acids, ketone bodies, glucose, lactate, and acetate. 1H NMR spectra from suspensions of intact hepatocytes incubated with acetaminophen showed no resonances for drug metabolites, although changes in sugar resonances were observed. However, spectra of extracts from acetaminophen-treated hepatocytes contained resonances for both acetaminophen itself and its major metabolites, the glucuronide and sulfate conjugates. Results on the extent of acetaminophen metabolism as measured by 1H NMR compared well with previously reported chromatographic studies. The rate of metabolism of acetaminophen by hepatocytes was much slower in 2H2O buffer compared to H2O buffer and selective deuteration of several metabolites including the ketone bodies, glucose, and acetaminophen glucuronide was observed. The deuteration of glucose C2H appeared to be due to futile cycling of the glycolytic pathway to at least fructose 6-phosphate, and incorporation of deuterium by the enzyme phosphoglucoisomerase. This work demonstrates that 1H NMR studies of intact hepatocytes and cell extracts together can provide considerable insight into the metabolism of acetaminophen in vitro. Little pretreatment of samples is required, results can be obtained rapidly, and both normal and drug metabolites can be observed simultaneously. Similar studies should be applicable to a wide range of other drugs.

Acetaminophen↗
PubMed1984

Acetylhydrazine hepatotoxicity: the role of covalent binding.

Acetylhydrazine, a human metabolite of isoniazid and a hepatotoxin, binds covalently to rat liver protein and to the proteins of other organs in vivo. The covalent binding to macromolecules in the liver, but not to those of other organs, was increased by pretreatment with phenobarbital. The time course of binding to total hepatic protein and to hepatic subcellular fractions was also altered by phenobarbital pretreatment. There was a concommitant time-dependent decline in cytochrome P-450 levels in the phenobarbital pretreated animals, but not controls. Acetylhydrazine did not produce detectable lesions in organs other than the liver, despite the occurrence of covalent binding to protein in those organs. The results suggest that only a critical fraction of the covalent binding to specific subcellular components is related to the subsequent development of tissue lesions.

Animals↗