Bernhard Lauterburg - Academia.edu (original) (raw)
Papers by Bernhard Lauterburg
Swiss medical weekly, 2010
Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large im... more Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation o...
Liver, 1988
Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might ... more Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might in part be responsible for ischemic organ injury. Therefore, the effect of allopurinol, an inhibitor of xanthine oxidase, on the oxidant stress associated with reperfusion and on hepatic function 24 h after ischemia was assessed in a model of partial hepatic ischemia in rats. The increase in circulating glutathione disulfide (GSSG) was used as an index of oxidant stress. Hepatic function was assessed using a breath test to quantitative the demethylation of aminopyrine in vivo. In control animals the plasma concentration of GSSG 1 h after onset of reperfusion increased from 0.9 mumol/l in sham-operated controls to 4.2, 5.5, and 8.0 mumol/l following 45, 90 and 120 min of ischemia, respectively. The percent of the administered dose of (dimethylamine-14C)-aminopyrine appearing in breath as 14CO2 was not significantly different from sham-operated controls (40.2%) 24 h after 45 min of ischemi...
Liver, 2008
Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might ... more Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might in part be responsible for ischemic organ injury. Therefore, the effect of allopurinol, an inhibitor of xanthine oxidase, on the oxidant stress associated with reperfusion and on hepatic function 24 h after ischemia was assessed in a model of partial hepatic ischemia in rats. The increase in circulating glutathione disulfide (GSSG) was used as an index of oxidant stress. Hepatic function was assessed using a breath test to quantitative the demethylation of aminopyrine in vivo. In control animals the plasma concentration of GSSG 1 h after onset of reperfusion increased from 0.9 mumol/l in sham-operated controls to 4.2, 5.5, and 8.0 mumol/l following 45, 90 and 120 min of ischemia, respectively. The percent of the administered dose of (dimethylamine-14C)-aminopyrine appearing in breath as 14CO2 was not significantly different from sham-operated controls (40.2%) 24 h after 45 min of ischemia (34.1%), but decreased progressively to 26.0% (p less than 0.05) and 20.6% (p less than 0.05) after 90 and 120 min of ischemia, respectively. Allopurinol, administered at a dose of 50 mg/kg 18 h and 1 h prior to ischemia, did not prevent the rise in plasma GSSG, did not alleviate the release of transaminases, and did not improve the demethylation of aminopyrine 24 h after ischemia, suggesting that reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver do not contribute significantly to ischemic injury.
Journal of Pharmacology and Experimental Therapeutics, 1984
Plasma GSH and GSSG concentrations were examined after the administration of compounds that deple... more Plasma GSH and GSSG concentrations were examined after the administration of compounds that deplete intracellular GSH either by adduct formation or by production of oxidative stress. A modified assay based on the GSSG reductase method was developed that minimizes the artifactual auto-oxidation of GSH to GSSG and mixed disulfides by rapid addition of bis(3-carboxy-4-nitrophenyl)disulfide or N-ethylmaleimide directly to whole blood or tissue samples. Control arterial plasma GSH and GSSG concentrations were found to be 16.5 +/- 0.7 and 0.3 +/- 0.1 microM, respectively. Depletion of GSH by fasting or by the administration of acetaminophen or diethyl maleate was associated with a proportional decrease in the arterial plasma GSH concentrations (r = 0.94) consistent with the hypothesis that the liver in vivo is a major source of plasma GSH. Diquat and t-butyl hydroperoxide, but not acetaminophen or diethyl maleate, elicited large increases in arterial plasma GSSG concentrations (17- and 115-fold, respectively) and several-fold increases in biliary GSSG levels without markedly increasing hepatic GSSG levels (2.7- and 1.2-fold, respectively). In contrast, treatment with paraquat produced substantial increases in arterial plasma GSSG levels (22-fold) without large increases in the bile (3-fold). Assessment of the arteriovenous difference for GSSG across the lungs after paraquat administration demonstrated that the lung may be a significant source of plasma GSSG. In conclusion, plasma GSH concentrations appear to reflect mainly intrahepatic GSH concentration, whereas plasma GSSG appears to arise from both hepatic and extrahepatic sites.(ABSTRACT TRUNCATED AT 250 WORDS)
American Journal of Therapeutics, 2002
A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cel... more A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cellular function. It detoxifies toxic metabolites of drugs and reactive oxygen species and regulates gene expression, apoptosis, and transmembrane transport of organic solutes. The maintenance of GSH homeostasis is essential for the organism to perform its many functions. The turnover of GSH is a dynamic process, and large quantities of GSH are synthesized per day from its precursor amino acids cysteine, glutamic acid, and glycine. Toxic doses of paracetamol deplete intracellular GSH and result in cell death by a combination of mechanisms, leading to necrosis and apoptosis, mainly in the liver. In clinical situations characterized by low GSH, the risk of toxicity from therapeutic doses of paracetamol may conceivably be increased. This toxicity has been reported in chronic alcoholics who have low intrahepatic GSH and who may have an induced enzyme system that generates the toxic metabolite of paracetamol. Considering the large number of alcoholics in our population and the widespread use of paracetamol, this must be a rare and essentially unpredictable occurrence. Except for anecdotal reports, there is no convincing evidence that other populations in which low GSH has been observed-such as patients with human immunodeficiency virus (HIV) infection or chronic hepatitis C, malnourished patients, and patients with cirrhosis-are at higher risk of experiencing adverse events from paracetamol.
Clinical Pharmacology and Therapeutics, Jun 1, 2005
Hepatology, 1991
Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and ... more Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p less than 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 +/- 0.03 vs. 0.67 +/- 0.07 nmol/mg protein; p less than 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil.
J Hepatol, 1989
The chemically rea.cti*e acetaldehyde generated during the metabolism of ethanol might coralently... more The chemically rea.cti*e acetaldehyde generated during the metabolism of ethanol might coralently bJ"d to pratelns and thereby a1tv the StvUCture and funct,on of cells and elicit an imm""olcgica; response. To test the hyparhesis that A-Ps are present in alcahol~cs. human plasma protein wds iocubated wrth 240mM acetaldehyde and the resulting Schiff bares were reduced. This incubation denvatlred ~3% of the lysine residues to ethyllys~ne as "enfled by GC-MS. Immumzat~on of a rabbit wth human A-P resulted I" the prod~ctio" of tp$'-A-P antibod,er which were isolated by affinity chrom.togr.~hy and labelled wth I. Plasma prote~nr modified in v,tro. a"d the glasma of 11 alcoholic s"bJXtS* of 9 non-drwking subjects and of R patrents wth non alcoholic liver disease was subjected to 50y25gel electrophor~ir.
Cancer Chemother Pharmacol, 1993
To test the feasibility of uroprotection with sodium 2-mercaptoethane-sulfonate (mesna) in tablet... more To test the feasibility of uroprotection with sodium 2-mercaptoethane-sulfonate (mesna) in tablet form the bioavailability of mesna tablets was determined in healthy volunteers by HPLC. The area under the plasma concentration-time curve (AUC) of free mesna was significantly lower following oral (110 mumol.l-1 x h-1; 95% CI 98-122) than following i.v. administration of 1.2 g of mesna (201 mumol.l-1 x h-1; 95% CI 158-244). The AUC for total mesna, i.e. dimesna and mixed disulfides, however, were comparable in the two groups, with 628 (539-717) and 772 (713-831) mumol.l-1 x h-1, respectively. The mean residence time was significantly longer following oral mesna, at 79 (76-83) min vs 239 (229-250) min. Following oral mesna 51.1% (46.2-56.0%) of the administered dose was recovered in the urine in 24 h, compared with 60.6 (53.6-67.6)% in 4 h following i.v. mesna, and the average concentration of mesna in the urine exceeded 3 mmol.l-1 for 8 h. The data indicate that mesna in tablet form has an adequate bioavailability for uroprotection and therefore may be preferable to liquid mesna, which has an unpleasant taste. Oral mesna has a longer mean residence time than i.v. mesna, which means that uroprotection can be achieved with longer dosing intervals.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, Aug 1, 1992
There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutat... more There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
Scandinavian Journal of Gastroenterology, May 1, 1990
Plasma levels of ammonia and amino acids were measured during and after graded physical exercise ... more Plasma levels of ammonia and amino acids were measured during and after graded physical exercise in seven ambulatory patients with well-compensated chronic liver disease and in seven healthy controls. Plasma ammonia was similar in both groups at rest but reached significantly higher peak values (124.0 +/- 29.3 (SD) versus 74.7 +/- 17.7 mumol/l) in the patients with liver disease during exercise. The return to base line during the recovery period was delayed in the patients (T1/2 9.9 +/- 5.5 versus 2.3 +/- 1.0 min). Except for plasma taurine, which was significantly lower in the patients at rest and which showed a significant decrease in the controls but not in the patients during exercise, changes in the plasma concentration of amino acids were similar in the two groups. The increased exposure of patients with chronic liver disease to ammonia while performing an identical workload results from an impaired clearance of ammonia plus, possibly, an increased generation of ammonia in muscle working at a higher intensity. Since hyperammonemia may be associated with the sensation of fatigue, increases in plasma ammonia during daily physical activities might in part explain the easy fatigability often reported by patients with chronic liver disease.
Journal of Laboratory and Clinical Medicine
ABSTRACT
Mayo Clinic Proceedings
The Mayo Clinic experience with more than 200 bile acid breath tests was analyzed retrospectively... more The Mayo Clinic experience with more than 200 bile acid breath tests was analyzed retrospectively to assess its clinical value. In patients with suspected bacterial overgrowth, the result of the bile acid breath test was compared with that of culture of aspirates of small bowel, and the test was found to have a sensitivity of 0.70 and a specificity of 0.90 (1.0 highest possible value). Although in one-third of the patients with a positive small-bowel culture the bile acid breath test failed to demonstrate the presence of bacterial overgrowth, analysis of the data according to the Bayes theorem showed that, compared with a routine evaluation without a small-bowel culture, the availability of breath test results will double the probability with which the clinician can be certain about the presence or absence of bacterial overgrowth. The test result appeared to influence the diagnosis in 83% and the management in 74% of the 163 patients in whom it was performed because of suspected bacterial overgrowth. In patients with suspected malabsorption of bile acids, on the other hand, the test that was performed without determination of fecal bile acid excretion appeared to be rather insensitive, and only rarely was information gained that was not already known from a routine workup of the patient.
Journal of Laboratory and Clinical Medicine
Studies in experimental animals and morphologic data in patients suggest that mitochondria are a ... more Studies in experimental animals and morphologic data in patients suggest that mitochondria are a prime target of the toxicity of ethanol and acetylsalicylic acid. However, the effects of socially consumed amounts of ethanol and therapeutic doses of acetylsalicylic acid on mitochondrial function in human beings are not known. The alpha-ketoisocaproic acid (KICA) breath test noninvasively assesses a mitochondrial function, the decarboxylation of KICA, by following the exhalation of labeled carbon dioxide after the administration of labeled KICA. The decarboxylation of I-[13C]KICA was measured in two groups of eight healthy volunteers after ingestion of 0.5 gm/kg of ethanol or 30 mg/kg of acetylsalicylic acid, respectively. Breath samples were collected at intervals for the determination of [13C] carbon dioxide in breath. The ingestion of ethanol resulted in peak concentrations of ethanol in plasma of 17.3 +/- 2.4 mmol/L (mean +/- 95% confidence interval) and increased the lactate/pyruvate ratio in peripheral venous blood. Although the 13C enrichment of circulating KICA and leucine were similar in the presence and absence of ethanol, the decarboxylation KICA was significantly lower (p < 0.01) at each time point in the presence of ethanol. The fraction decarboxylated in 2 hours was 6.3% +/- 1.9% of the administered dose after administration of ethanol and 14.2% +/- 3.9% (p < 0.001) in the control period. In contrast, the ingestion of acetylsalicylic acid, which resulted in plasma concentrations of 0.9 mmol/L salicylate significantly increased the decarboxylation of KICA to 19.3% +/- 3.1% of the administered dose exhaled in 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Pharmacology and Experimental Therapeutics
Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into... more Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into cell cytosol and therefore might have therapeutic potential in states of GSH deficiency. To better understand the disposition of GSHE, the pharmacokinetics of GSHE and GSH were compared in rats. Fifteen min after an i.v. dose of 5 mmol/kg GSHE, the plasma concentration of GSHE was 7.2 +/- 1.2 mmol/l and the plasma concentration of GSH had increased from 0.009 +/- 0.002 to 2.5 +/- 0.3 mmol/l. The areas under the plasma concentration time curves of GSH were identical after either the administration of GSHE or GSH, but the mean residence time of GSH in plasma was significantly longer after GSHE. The concentration of GSHE in liver reached a peak of 0.66 +/- 0.09 mumol/g. Intrahepatic concentrations of cysteine and GSH increased from 53 +/- 15 to 319 +/- 41 nmol/g and from 5.5 +/- 0.4 to 7.8 +/- 1.5 mumol/g, respectively, and remained elevated for 2 hr. Similar increases occurred after administration of GSH. However, the concentrations of cysteine and GSH peaked earlier and had returned to baseline by 2 hr. Qualitatively similar results were obtained in rats pretreated with L-buthionine-[S, R]-sulfoximine that partially inhibits GSH synthesis. GSHE added to rat plasma at a concentration of 10 mM was hydrolyzed to GSH at a rate of 0.1 mumol/min. Our data indicate that GSHE is not readily taken up by the liver, but is hydrolyzed by esterases in plasma and thereby gradually releases GSH in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)
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](Schweizerische Rundschau fur Medizin Praxis = Revue suisse de medecine Praxis
Journal of Pharmacology and Experimental Therapeutics
The role of GSH in the detoxification of reactive metabolites of oxygen and xenobiotics, in gene ... more The role of GSH in the detoxification of reactive metabolites of oxygen and xenobiotics, in gene expression, and as a source of cysteine is well established. Because decreased circulating and intracellular concentrations of GSH might be of pathogenetic relevance in several clinical conditions, there is a growing interest in pharmacological interventions to correct a deranged sulfhydryl status. In this study, the disposition and the effect of S,N-diacetylcysteine monoethyl ester (DACE) on sulfhydryls were investigated after i.v. and intraduodenal (i.d.) administrations to rats. DACE was rapidly hydrolyzed and deacetylated to N-acetylcysteine and cysteine in plasma. High concentrations of cysteine were attained in the circulation and in the liver after i.v. and i.d. administrations of 5 mmol/kg DACE, and physiological levels of GSH in the liver and in plasma increased by 30 and 300%, respectively, with i.v. and i.d. administrations. Incubation of peripheral blood mononuclear cells with 1 mM DACE resulted in higher intracellular concentrations of cysteine and GSH after 24 h than incubations with equimolar concentrations of cysteine, N-acetylcysteine, or oxothiazolidine carboxylic acid, respectively. It is concluded that DACE provides an efficient delivery system for cysteine that markedly increases intra- and extracellular cysteine and GSH after i.v. and i.d. administrations. Because its uptake into cells is probably not dependent on an active transport process, DACE results in higher intracellular concentrations of cysteine than those resulting from other prodrugs of cysteine and cysteine itself. The compound may thus have advantages over other compounds for the correction of a deranged sulfhydryl status.
Swiss medical weekly, 2010
Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large im... more Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation o...
Liver, 1988
Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might ... more Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might in part be responsible for ischemic organ injury. Therefore, the effect of allopurinol, an inhibitor of xanthine oxidase, on the oxidant stress associated with reperfusion and on hepatic function 24 h after ischemia was assessed in a model of partial hepatic ischemia in rats. The increase in circulating glutathione disulfide (GSSG) was used as an index of oxidant stress. Hepatic function was assessed using a breath test to quantitative the demethylation of aminopyrine in vivo. In control animals the plasma concentration of GSSG 1 h after onset of reperfusion increased from 0.9 mumol/l in sham-operated controls to 4.2, 5.5, and 8.0 mumol/l following 45, 90 and 120 min of ischemia, respectively. The percent of the administered dose of (dimethylamine-14C)-aminopyrine appearing in breath as 14CO2 was not significantly different from sham-operated controls (40.2%) 24 h after 45 min of ischemi...
Liver, 2008
Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might ... more Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might in part be responsible for ischemic organ injury. Therefore, the effect of allopurinol, an inhibitor of xanthine oxidase, on the oxidant stress associated with reperfusion and on hepatic function 24 h after ischemia was assessed in a model of partial hepatic ischemia in rats. The increase in circulating glutathione disulfide (GSSG) was used as an index of oxidant stress. Hepatic function was assessed using a breath test to quantitative the demethylation of aminopyrine in vivo. In control animals the plasma concentration of GSSG 1 h after onset of reperfusion increased from 0.9 mumol/l in sham-operated controls to 4.2, 5.5, and 8.0 mumol/l following 45, 90 and 120 min of ischemia, respectively. The percent of the administered dose of (dimethylamine-14C)-aminopyrine appearing in breath as 14CO2 was not significantly different from sham-operated controls (40.2%) 24 h after 45 min of ischemia (34.1%), but decreased progressively to 26.0% (p less than 0.05) and 20.6% (p less than 0.05) after 90 and 120 min of ischemia, respectively. Allopurinol, administered at a dose of 50 mg/kg 18 h and 1 h prior to ischemia, did not prevent the rise in plasma GSSG, did not alleviate the release of transaminases, and did not improve the demethylation of aminopyrine 24 h after ischemia, suggesting that reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver do not contribute significantly to ischemic injury.
Journal of Pharmacology and Experimental Therapeutics, 1984
Plasma GSH and GSSG concentrations were examined after the administration of compounds that deple... more Plasma GSH and GSSG concentrations were examined after the administration of compounds that deplete intracellular GSH either by adduct formation or by production of oxidative stress. A modified assay based on the GSSG reductase method was developed that minimizes the artifactual auto-oxidation of GSH to GSSG and mixed disulfides by rapid addition of bis(3-carboxy-4-nitrophenyl)disulfide or N-ethylmaleimide directly to whole blood or tissue samples. Control arterial plasma GSH and GSSG concentrations were found to be 16.5 +/- 0.7 and 0.3 +/- 0.1 microM, respectively. Depletion of GSH by fasting or by the administration of acetaminophen or diethyl maleate was associated with a proportional decrease in the arterial plasma GSH concentrations (r = 0.94) consistent with the hypothesis that the liver in vivo is a major source of plasma GSH. Diquat and t-butyl hydroperoxide, but not acetaminophen or diethyl maleate, elicited large increases in arterial plasma GSSG concentrations (17- and 115-fold, respectively) and several-fold increases in biliary GSSG levels without markedly increasing hepatic GSSG levels (2.7- and 1.2-fold, respectively). In contrast, treatment with paraquat produced substantial increases in arterial plasma GSSG levels (22-fold) without large increases in the bile (3-fold). Assessment of the arteriovenous difference for GSSG across the lungs after paraquat administration demonstrated that the lung may be a significant source of plasma GSSG. In conclusion, plasma GSH concentrations appear to reflect mainly intrahepatic GSH concentration, whereas plasma GSSG appears to arise from both hepatic and extrahepatic sites.(ABSTRACT TRUNCATED AT 250 WORDS)
American Journal of Therapeutics, 2002
A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cel... more A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cellular function. It detoxifies toxic metabolites of drugs and reactive oxygen species and regulates gene expression, apoptosis, and transmembrane transport of organic solutes. The maintenance of GSH homeostasis is essential for the organism to perform its many functions. The turnover of GSH is a dynamic process, and large quantities of GSH are synthesized per day from its precursor amino acids cysteine, glutamic acid, and glycine. Toxic doses of paracetamol deplete intracellular GSH and result in cell death by a combination of mechanisms, leading to necrosis and apoptosis, mainly in the liver. In clinical situations characterized by low GSH, the risk of toxicity from therapeutic doses of paracetamol may conceivably be increased. This toxicity has been reported in chronic alcoholics who have low intrahepatic GSH and who may have an induced enzyme system that generates the toxic metabolite of paracetamol. Considering the large number of alcoholics in our population and the widespread use of paracetamol, this must be a rare and essentially unpredictable occurrence. Except for anecdotal reports, there is no convincing evidence that other populations in which low GSH has been observed-such as patients with human immunodeficiency virus (HIV) infection or chronic hepatitis C, malnourished patients, and patients with cirrhosis-are at higher risk of experiencing adverse events from paracetamol.
Clinical Pharmacology and Therapeutics, Jun 1, 2005
Hepatology, 1991
Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and ... more Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p less than 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 +/- 0.03 vs. 0.67 +/- 0.07 nmol/mg protein; p less than 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil.
J Hepatol, 1989
The chemically rea.cti*e acetaldehyde generated during the metabolism of ethanol might coralently... more The chemically rea.cti*e acetaldehyde generated during the metabolism of ethanol might coralently bJ"d to pratelns and thereby a1tv the StvUCture and funct,on of cells and elicit an imm""olcgica; response. To test the hyparhesis that A-Ps are present in alcahol~cs. human plasma protein wds iocubated wrth 240mM acetaldehyde and the resulting Schiff bares were reduced. This incubation denvatlred ~3% of the lysine residues to ethyllys~ne as "enfled by GC-MS. Immumzat~on of a rabbit wth human A-P resulted I" the prod~ctio" of tp$'-A-P antibod,er which were isolated by affinity chrom.togr.~hy and labelled wth I. Plasma prote~nr modified in v,tro. a"d the glasma of 11 alcoholic s"bJXtS* of 9 non-drwking subjects and of R patrents wth non alcoholic liver disease was subjected to 50y25gel electrophor~ir.
Cancer Chemother Pharmacol, 1993
To test the feasibility of uroprotection with sodium 2-mercaptoethane-sulfonate (mesna) in tablet... more To test the feasibility of uroprotection with sodium 2-mercaptoethane-sulfonate (mesna) in tablet form the bioavailability of mesna tablets was determined in healthy volunteers by HPLC. The area under the plasma concentration-time curve (AUC) of free mesna was significantly lower following oral (110 mumol.l-1 x h-1; 95% CI 98-122) than following i.v. administration of 1.2 g of mesna (201 mumol.l-1 x h-1; 95% CI 158-244). The AUC for total mesna, i.e. dimesna and mixed disulfides, however, were comparable in the two groups, with 628 (539-717) and 772 (713-831) mumol.l-1 x h-1, respectively. The mean residence time was significantly longer following oral mesna, at 79 (76-83) min vs 239 (229-250) min. Following oral mesna 51.1% (46.2-56.0%) of the administered dose was recovered in the urine in 24 h, compared with 60.6 (53.6-67.6)% in 4 h following i.v. mesna, and the average concentration of mesna in the urine exceeded 3 mmol.l-1 for 8 h. The data indicate that mesna in tablet form has an adequate bioavailability for uroprotection and therefore may be preferable to liquid mesna, which has an unpleasant taste. Oral mesna has a longer mean residence time than i.v. mesna, which means that uroprotection can be achieved with longer dosing intervals.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, Aug 1, 1992
There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutat... more There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
Scandinavian Journal of Gastroenterology, May 1, 1990
Plasma levels of ammonia and amino acids were measured during and after graded physical exercise ... more Plasma levels of ammonia and amino acids were measured during and after graded physical exercise in seven ambulatory patients with well-compensated chronic liver disease and in seven healthy controls. Plasma ammonia was similar in both groups at rest but reached significantly higher peak values (124.0 +/- 29.3 (SD) versus 74.7 +/- 17.7 mumol/l) in the patients with liver disease during exercise. The return to base line during the recovery period was delayed in the patients (T1/2 9.9 +/- 5.5 versus 2.3 +/- 1.0 min). Except for plasma taurine, which was significantly lower in the patients at rest and which showed a significant decrease in the controls but not in the patients during exercise, changes in the plasma concentration of amino acids were similar in the two groups. The increased exposure of patients with chronic liver disease to ammonia while performing an identical workload results from an impaired clearance of ammonia plus, possibly, an increased generation of ammonia in muscle working at a higher intensity. Since hyperammonemia may be associated with the sensation of fatigue, increases in plasma ammonia during daily physical activities might in part explain the easy fatigability often reported by patients with chronic liver disease.
Journal of Laboratory and Clinical Medicine
ABSTRACT
Mayo Clinic Proceedings
The Mayo Clinic experience with more than 200 bile acid breath tests was analyzed retrospectively... more The Mayo Clinic experience with more than 200 bile acid breath tests was analyzed retrospectively to assess its clinical value. In patients with suspected bacterial overgrowth, the result of the bile acid breath test was compared with that of culture of aspirates of small bowel, and the test was found to have a sensitivity of 0.70 and a specificity of 0.90 (1.0 highest possible value). Although in one-third of the patients with a positive small-bowel culture the bile acid breath test failed to demonstrate the presence of bacterial overgrowth, analysis of the data according to the Bayes theorem showed that, compared with a routine evaluation without a small-bowel culture, the availability of breath test results will double the probability with which the clinician can be certain about the presence or absence of bacterial overgrowth. The test result appeared to influence the diagnosis in 83% and the management in 74% of the 163 patients in whom it was performed because of suspected bacterial overgrowth. In patients with suspected malabsorption of bile acids, on the other hand, the test that was performed without determination of fecal bile acid excretion appeared to be rather insensitive, and only rarely was information gained that was not already known from a routine workup of the patient.
Journal of Laboratory and Clinical Medicine
Studies in experimental animals and morphologic data in patients suggest that mitochondria are a ... more Studies in experimental animals and morphologic data in patients suggest that mitochondria are a prime target of the toxicity of ethanol and acetylsalicylic acid. However, the effects of socially consumed amounts of ethanol and therapeutic doses of acetylsalicylic acid on mitochondrial function in human beings are not known. The alpha-ketoisocaproic acid (KICA) breath test noninvasively assesses a mitochondrial function, the decarboxylation of KICA, by following the exhalation of labeled carbon dioxide after the administration of labeled KICA. The decarboxylation of I-[13C]KICA was measured in two groups of eight healthy volunteers after ingestion of 0.5 gm/kg of ethanol or 30 mg/kg of acetylsalicylic acid, respectively. Breath samples were collected at intervals for the determination of [13C] carbon dioxide in breath. The ingestion of ethanol resulted in peak concentrations of ethanol in plasma of 17.3 +/- 2.4 mmol/L (mean +/- 95% confidence interval) and increased the lactate/pyruvate ratio in peripheral venous blood. Although the 13C enrichment of circulating KICA and leucine were similar in the presence and absence of ethanol, the decarboxylation KICA was significantly lower (p < 0.01) at each time point in the presence of ethanol. The fraction decarboxylated in 2 hours was 6.3% +/- 1.9% of the administered dose after administration of ethanol and 14.2% +/- 3.9% (p < 0.001) in the control period. In contrast, the ingestion of acetylsalicylic acid, which resulted in plasma concentrations of 0.9 mmol/L salicylate significantly increased the decarboxylation of KICA to 19.3% +/- 3.1% of the administered dose exhaled in 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Pharmacology and Experimental Therapeutics
Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into... more Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into cell cytosol and therefore might have therapeutic potential in states of GSH deficiency. To better understand the disposition of GSHE, the pharmacokinetics of GSHE and GSH were compared in rats. Fifteen min after an i.v. dose of 5 mmol/kg GSHE, the plasma concentration of GSHE was 7.2 +/- 1.2 mmol/l and the plasma concentration of GSH had increased from 0.009 +/- 0.002 to 2.5 +/- 0.3 mmol/l. The areas under the plasma concentration time curves of GSH were identical after either the administration of GSHE or GSH, but the mean residence time of GSH in plasma was significantly longer after GSHE. The concentration of GSHE in liver reached a peak of 0.66 +/- 0.09 mumol/g. Intrahepatic concentrations of cysteine and GSH increased from 53 +/- 15 to 319 +/- 41 nmol/g and from 5.5 +/- 0.4 to 7.8 +/- 1.5 mumol/g, respectively, and remained elevated for 2 hr. Similar increases occurred after administration of GSH. However, the concentrations of cysteine and GSH peaked earlier and had returned to baseline by 2 hr. Qualitatively similar results were obtained in rats pretreated with L-buthionine-[S, R]-sulfoximine that partially inhibits GSH synthesis. GSHE added to rat plasma at a concentration of 10 mM was hydrolyzed to GSH at a rate of 0.1 mumol/min. Our data indicate that GSHE is not readily taken up by the liver, but is hydrolyzed by esterases in plasma and thereby gradually releases GSH in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)
Schweizerische Rundschau fur Medizin Praxis = Revue suisse de medecine Praxis
Journal of Pharmacology and Experimental Therapeutics
The role of GSH in the detoxification of reactive metabolites of oxygen and xenobiotics, in gene ... more The role of GSH in the detoxification of reactive metabolites of oxygen and xenobiotics, in gene expression, and as a source of cysteine is well established. Because decreased circulating and intracellular concentrations of GSH might be of pathogenetic relevance in several clinical conditions, there is a growing interest in pharmacological interventions to correct a deranged sulfhydryl status. In this study, the disposition and the effect of S,N-diacetylcysteine monoethyl ester (DACE) on sulfhydryls were investigated after i.v. and intraduodenal (i.d.) administrations to rats. DACE was rapidly hydrolyzed and deacetylated to N-acetylcysteine and cysteine in plasma. High concentrations of cysteine were attained in the circulation and in the liver after i.v. and i.d. administrations of 5 mmol/kg DACE, and physiological levels of GSH in the liver and in plasma increased by 30 and 300%, respectively, with i.v. and i.d. administrations. Incubation of peripheral blood mononuclear cells with 1 mM DACE resulted in higher intracellular concentrations of cysteine and GSH after 24 h than incubations with equimolar concentrations of cysteine, N-acetylcysteine, or oxothiazolidine carboxylic acid, respectively. It is concluded that DACE provides an efficient delivery system for cysteine that markedly increases intra- and extracellular cysteine and GSH after i.v. and i.d. administrations. Because its uptake into cells is probably not dependent on an active transport process, DACE results in higher intracellular concentrations of cysteine than those resulting from other prodrugs of cysteine and cysteine itself. The compound may thus have advantages over other compounds for the correction of a deranged sulfhydryl status.