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At least 19 recordsLinked to original sources
PubMed1996

Detection of two metabolites of diquat in urine and serum of poisoned patients after ingestion of a combined herbicide of paraquat and diquat.

This report describes the identification of diquat-dipyridone and diquat-monopyridone as metabolites of diquat, and time course changes of these metabolites plus diquat and paraquat in urine and serum of three poisoned patients who ingested the combination herbicide Preeglox L (containing 5% paraquat dichloride and 7% diquat dibromide) in a suicide attempt. Diquat-dipyridone was isolated from urine and identified by electron impact mass spectrometry, thin layer chromatography and high performance liquid chromatography (HPLC). Diquat-monopyridone, diquat-dipyridone, diquat and paraquat in serum and urine were assayed by HPLC with fluorescence and UV detection. Paraquat-monopyridone as a metabolite of paraquat was not detected in any samples. These results indicate that diquat is metabolized to diquat-monopyridone and diquat-dipyridone and also that the metabolism of diquat is easier than that of paraquat in humans. The concentrations of each metabolite were always lower than that of diquat in each specimen. However, the ratios of the concentration of each metabolite against the concentration of diquat increased with the decrease of diquat concentration. The metabolism of diquat seems to lower slightly the diquat concentration.

Chromatography, High Pressure Liquid↗
PubMed2002

Analysis of paraquat, diquat and two diquat metabolites in biological materials by high-performance liquid chromatography.

The determination of paraquat, diquat and two metabolites of diquat in biological materials was developed using high-performance liquid chromatography combined with UV and fluorescence detectors. Paraquat, diquat and internal standards (ethyl viologen and o-acetamidophenol) were detected by the UV detector. Diquat-monopyridone and diquat-dipyridone were monitored by the fluorescence detector. Paraquat, diquat, diquat-monopyridone and ethyl viologen were effectively extracted from blood, liver and brain, using a Sep-Pak C(18) cartridge. Diquat-dipyridone and o-acetamidophenol were extracted with methanol. Paraquat and diquat at a concentration range of 0.1-10 microg/ml (or g), and diquat-monopyridone and diquat-dipyridone at a concentration range of 0.01-1 microg/ml (or g) in biological material were determined with high accuracy and precision. The detection limits of paraquat, diquat, diquat-monopyridone and diquat-dipyridone were 1, 1, 0.02 and 0.02 ng, respectively, as an injection amount. This method was applied for toxicological examination of a case of suspected paraquat and diquat intoxication. The analysis of the metabolites of diquat was helpful for the estimation of the elapsed time from ingestion to death.

Journal Article↗
PubMed1993

[In vitro studies of the metabolism of paraquat and diquat using rat liver homogenates--isolation and identification of the metabolites of paraquat and diquat].

The metabolism of paraquat and diquat was studied in vitro using rat liver homogenates, and the resulting metabolites were identified. Rat liver was homogenized with three volumes of isotonic buffer, and aliquots of the homogenate were preheated in a boiling water bath for 5 min prior to use. One milliliter of a mixture including both paraquat and diquat in an isotonic buffer solution (10 micrograms ion/ml) was incubated with an equal volume of fresh or preheated homogenate for 1 to 60 min at 37 degrees C. Quantification of paraquat and diquat was carried out by high-performance liquid chromatography (HPLC). In the fresh homogenate, a gradual decrease of paraquat concentration (about a 30% decrease over 60 min of incubation) and a rapid decrease of diquat concentration (not detectable after 10 min of incubation) were observed, but the same phenomenon was not evident with the preheated homogenate. Analysis of the incubated mixture of fresh liver homogenate with paraquat and diquat revealed three unknown peaks on the HPLC chromatograms; these seemed to be breakdown products of paraquant and diquat. The products were isolated and purified from the mixture by Sep-Pak C18 cartridge extraction, HPLC, silica gel column chromatography and Sephadex LH-20 column chromatography. Analysis of the chemical structure of the purified compounds was performed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. These analyses determined that paraquat-monopyridone (1',2'-dihydro-1,1'-dimethyl-2-oxo-4,4'-bipyridylium ion) was derived from paraquat, and that diquat-monopyridone (6,7-dihydro-4-oxodipyrido [1,2-a':2',1'-c] pyrazinium ion) and diquat-dipyridone (6,7-dihydrodipyrido [1,2-a:2',1'-c] pyrazine-4,9-dione) were derived from diquat. These results indicate that paraquat and diquat are metabolized by rat liver homogenate, diquat more readily so than paraquat. As the toxicity of these metabolites has been reported to be much lower than those of the parental compounds, it would seem that there is a system capable of detoxifying paraquat and diquat in rat liver.

Animals↗
PubMed1992

Marked interanimal differences in susceptibility of Sprague-Dawley rats to diquat-induced oxidative stress in the liver: correlation with hepatic uptake of diquat.

Biliary excretion of oxidized glutathione (GSSG) is used as an index of oxidative stress. We observed a marked interanimal difference in susceptibility to diquat-induced oxidative stress. When diquat injections (120 mumol/kg, i.v.) were administered to rats, a 60-fold increase in the biliary excretion of GSSG was observed in 40% of the rats (responders); however, diquat failed to increase the biliary excretion of GSSG in 60% of the animals (nonresponders). This interanimal variation is not due to differences in the hepatic metabolism or hepatobiliary transport of GSSG, as no interanimal difference was observed in the biliary output of GSSG after administration of another oxidative stress-inducing agent, t-butyl hydroperoxide (1.4 mmol/kg, i.v.). We then examined the hepatobiliary disposition of diquat (120 mumol/kg, i.v.) using a high-performance liquid chromatography procedure to quantitate diquat in blood, liver and bile. No differences in blood or biliary concentration of diquat were noted between responders and nonresponders. However, a marked difference was observed in the hepatic concentration of diquat in responders and nonresponders. The responders exhibited a 4-fold higher hepatic diquat concentration than the nonresponders (65 or 15 nmol/g, respectively) 30 min after diquat administration. In conclusion, this study demonstrates a marked interanimal variation in the susceptibility of Sprague-Dawley rats to oxidative stress produced by diquat, which appears to be due to interanimal difference in the hepatic accumulation of diquat.

Animals↗
PubMed2000

A new diquat derivative appropriate for colourimetric measurements of biological materials in the presence of paraquat.

A new colourimetric method is described for the quantification of diquat using a yellow-coloured derivative produced by heating diquat in alkaline solution at 80 degrees C. The absorption maximum of the yellow derivative is 420 nm and the molar absorption coefficient is 2.76 x 10(4) (0.15 in 1 microgram diquat/ml with 1 cm light path). The absorption at 420 nm shows a linear concentration dependence in the range 0.1-10 micrograms/ml and fading of the colour is about 5% after 1 h. Under the same conditions, paraquat does not produce any coloured products. The concentration of diquat in the solution containing both diquat and paraquat can be determined by the absorption of diquat derivative at 420 nm without interference from paraquat. By adding sodium dithionite to the solution the concentration of paraquat can be determined by the absorption of paraquat radicals at 600 nm without interference from diquat, because the yellow derivative does not react with dithionite. This yellow diquat derivative can be extracted completely with cyclohexanol by saturating the solution with Na2SO4. The absorption maximum in cyclohexanol shifts to 440 nm with the same molar absorbance and the same half-band width as in water. Fading of the colour is less than 5% after 24 h in cyclohexanol. Perchloric acid (3%) and trichloroacetic acid (4.5%) which are often used for deproteinization of tissue homogenates, do not inhibit production of the coloured derivative at pH 13.5 or extraction of the derivative with cyclohexanol. This method is suitable for a quick determination of small amounts of diquat in tissues, since the extraction with cyclohexanol not only concentrates the derivative rapidly but also quite efficiently eliminates the coloured substances in tissue homogenates. The detection limit of diquat is 0.02 microgram/ml for blood and 0.05 microgram/g for liver when 1 ml or 1 g is used for analysis. In three human cases of fatal intoxication, both paraquat and diquat were quantified using 50 microliters of serum. In non-toxic dosing of diquat to rats for 14 days, the diquat level was highest in the spleen followed by the kidneys.

Animals↗
PubMed2002

Effect of diquat on the antioxidant system and cell growth in human neuroblastoma cells.

Oxidative stress elicits an adaptive antioxidant response, which varies with tissue type. Diquat, a potent redox cycler that generates reactive oxygen species, has been used to study oxidative stress; however, its effect on the antioxidant system has not been characterized in neuronal cells. Accordingly, we measured antioxidant parameters and cell growth in human neuroblastoma SH-SY5Y cells cultured for 48 h in medium containing 5, 10, or 25 microM diquat dibromide or phosphate-buffered saline. Viable cells were assayed for glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPX), and glucose-6-phosphate dehydrogenase (GPDH). Mitochondrial function was evaluated by glutamate dehydrogenase (GDH) activity and MTT reduction. Diquat caused a marked concentration-related decrease in viable cell count ( by 26, 51, and 87% at 5, 10, and 25 microM diquat). Cell viability was only affected at 10 and 25 microM diquat and did not fully account for the decreased viable cell count. Concentration-related increases also occurred with GSH levels and a majority of antioxidant enzymes activities; however, the mode and magnitude varied with parameter. Increases in GSH, CAT, SOD, and GR were maximal at 25 microM diquat (to 3-, 6-, 2-, and 1.5-fold control values, respectively). GPDH activity was maximal at 10 microM diquat and then decreased to 86% of control activity at 25 microM diquat. GPX activity showed a concentration-related decrease (to 35% of control). Activity of the mitochondrial enzyme GDH increased 3-fold at 25 microM diquat, along with a lesser increase in MTT reduction. We conclude that diquat reduces cell growth in neuroblastoma cells and induces an adaptive antioxidant response, which are concentration dependent and occur at sublethal concentrations. At higher concentrations, diquat alters mitochondrial function and becomes increasingly toxic.

Antioxidants↗
PubMed1992

Antioxidant-dependent inhibition of diquat-induced toxicity in vivo.

The abilities of two experimental antioxidants (U-74006F and U-78517G), as well as the model antioxidant, diphenyl-p-phenylenediamine (DPPD), to protect against diquat-induced toxicity in male Fischer-344 rats were examined. Both experimental compounds afforded near complete protection against diquat-induced hepatotoxicity, as measured by clinical chemistry and histopathological indices. When observed, diquat-induced nephrotoxicity was also inhibited. Minimal protection was afforded by the model compound, DPPD. In follow-up studies with U-78517G, no effect on diquat-induced biliary excretion of oxidized glutathione was observed, suggesting that a shift in the thiol:disulfide ratio is not responsible for diquat-induced hepatotoxicity. These data are consistent with those from previous in vitro studies in our laboratory and are in agreement with studies by others which suggest that lipid peroxidation is an important event in diquat-induced hepatotoxicity in vivo. The antioxidant effects were largely route-independent as either oral pre-treatment alone (200 mg/kg, 24 h before diquat), intravenous pre-treatment alone (6 mg/kg, 5 min before diquat) or the combination of both treatments produced a similar degree of protection. While pre-treatment with antioxidants was quite effective, no significant U-78517G-dependent inhibition of toxicity was observed when administration was delayed by as little as 10 min post diquat. These latter data suggest that initiation of diquat-induced hepatotoxicity is rapid and that these compounds would therefore be unlikely to have clinical utility in the treatment of diquat intoxication.

Alanine Transaminase↗
PubMed1983

Hemoperfusion in a child who ingested diquat and died from pontine infarction and hemorrhage.

A 2 1/2 year old boy accidentally ingested the herbicide diquat. Progressive neurologic dysfunction preceded his death 143 hours after poisoning. Brain stem infarction and purpura were noted at post mortem and closely resembled the brain stem pathology in 3 of 7 adults who died after diquat ingestion. Renal, gastrointestinal and pulmonary involvement in this child also resembled that seen in adults after ingestion of diquat. Hemoperfusion was performed six times in an effort to lower the body diquat burden. Cellulose-coated, activated charcoal was first employed 40 hours postingestion and removed diquat from serum with clearances of 104 and 39 ml/minute at the initiation of hemoperfusion and 6 hours later, respectively. Serum diquat concentrations decreased rapidly during charcoal hemoperfusion. However, marked rebound in serum diquat concentrations were noted between charcoal treatments, indicating extensive sequestration of diquat by tissues. Thrombocytopenia and hypocalcemia, the major complications of charcoal hemoperfusion, were easily treated. Unlike charcoal, Amberlite XAD-4 resin hemoperfusion did not remove diquat from serum. Charcoal hemoperfusion may temporarily reduce serum diquat concentrations. Whether the early institution and daily performance of charcoal hemoperfusion will minimize diquat-induced damage to brain and other organs is not clear from this case and will only be determined in future studies.

Adolescent↗
PubMed1988

Liver membrane calcium transport in diquat-induced oxidative stress in vivo.

Hepatic necrosis is produced rapidly by 0.1 mmol/kg diquat in male Fischer-344 rats but not Sprague-Dawley rats, yet massive oxidant stress is caused by diquat in both strains of rat. Liver plasma membrane calcium uptake was unaltered by diquat treatment in either strain. However, diquat inhibited ATP-dependent calcium sequestration by hepatic microsomes from Fischer rats by 33% (33 +/- 2 versus 50 +/- 2 nmol/mg/20 min), whereas liver microsomal calcium uptake in Sprague-Dawley rats was not decreased by diquat treatment. Microsomes of diquat-treated Fischer rats showed marked increases in calcium efflux versus controls (k efflux = 0.115 +/- 0.027 versus 0.051 +/- 0.005 min-1; p less than 0.025), but microsomes of diquat-treated Sprague-Dawley rats exhibited no significant change in efflux rate. Calcium uptake by the endoplasmic reticulum of saponin-permeabilized isolated hepatocytes was diminished in parallel with diquat cytotoxicity. Significant increases in 11-, 12-, and 15-hydroxy 20:4 fatty acids were found in liver microsomes isolated after diquat treatment in vivo and administration of desferrioxamine (0.24 mmol/kg, intraperitoneally) administered before diquat significantly protected against the inhibition of microsomal calcium uptake. These data suggest a possible role for Fenton chemistry and lipid peroxidation in this feature of diquat-generated hepatic damage in vivo.

Animals↗
PubMed1987

Evidence for participation of lipid peroxidation and iron in diquat-induced hepatic necrosis in vivo.

The hepatic necrosis produced in Fischer-344 rats by diquat appears to be mediated by redox cycling of diquat with generation of reactive oxygen species. We have now tested the hypothesis that chelates of iron are important in the cytotoxicity of reactive oxygen species, possibly through initiating the cleavage of peroxyl bonds. Pretreatment with the iron chelator desferrioxamine, 0.24 mmol/kg intraperitoneally, attenuated the hepatic damage produced by diquat. No additional protection was provided by a second dose of desferrioxamine 2 hr after diquat or by administration of the iron chelator by a different route of administration (subcutaneously). Ferrous sulfate (0.36 mmol/kg, intraperitoneally) alone produced no hepatic injury, but when given 15 min before diquat, it potentiated hepatic injury and animal mortality. In contrast, biliary excretion of glutathione disulfide in response to administration of diquat was neither potentiated by pretreatment with FeSO4 nor diminished by pretreatment with desferrioxamine. The marked changes in hepatic injury produced by these pretreatments, without changes in glutathione disulfide production, indicate that shifts in thiol/disulfide equilibria are not likely to be initiating events in the pathogenesis of diquat-induced hepatic necrosis. Administration of a hepatotoxic dose of diquat quickly produced 5-fold stimulation of ethane and pentane expiration rates with return to control rates by 3 hr. Desferrioxamine markedly inhibited, and iron potentiated, hydrocarbon expiration in response to diquat. The parallel changes in diquat hepatic injury and ethane and pentane expiration rates in response to manipulation of iron availability suggest a possible causal role for Fenton chemistry and lipid peroxidation in diquat-generated, reactive oxygen-mediated hepatic injury in vivo.

Animals↗
PubMed1988

Lethal injury by diquat redox cycling in an isolated hepatocyte model.

Hepatocyte isolated by collagenase perfusion of livers of male Fischer-344 rats, and treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (50 microM for 30 min at 37 degrees C) to inhibit glutathione reductase, were significantly more vulnerable to cytotoxicity of the bipyridyl herbicide diquat than similarly treated cells of Sprague-Dawley rats. Without compromise of cell defenses by BCNU, diquat was not cytotoxic to hepatocytes from either strain. Microsomal enzyme induction with phenobarbital (80 mg/kg ip for 3 days before hepatocyte isolation) did not potentiate killing of Fischer hepatocytes by diquat. Specific activities of NADPH-cytochrome P-450 reductase in isolated Fischer and Sprague-Dawley rat liver microsomes utilizing 1 mM diquat as acceptor were 0.085 +/- 0.017 and 0.076 +/- 0.028 mumol/mg.min (mean +/- SEM, N = 5), respectively, indicating the capacity for very active redox cycling of diquat by this route in both strains. The serine protease inhibitor, phenylmethylsulfonyl fluoride (100 microM), had no effect on diquat cytotoxicity, but both leupeptin (100 micrograms/ml) and antipain (50 or 100 microM) were able to delay, through not completely prevent, diquat-induced cell death. The phospholipase inhibitors, chlorpromazine (50 or 100 microM) and dibucaine (50 or 100 microM), similarly delayed but did not prevent cell death. Diquat increased the rate of hepatocyte phospholipid hydrolysis, measured as release into the suspending medium of [14C]arachidonic acid previously incorporated into hepatocyte lipids, but although chlorpromazine decreased phospholipid hydrolysis to the control rate, only partial protection against diquat cytotoxicity was seen. These data suggest that activation of phospholipase A2 and proteases by elevation of cytosolic free Ca2+ cannot account entirely for the loss of cell viability observed in the presence of cytotoxic concentrations of diquat.

Animals↗
PubMed1994

Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats.

The effects of diquat on the biliary efflux of nonheme iron in rats were studied as a means of examining the possible effects of diquat metabolism on hepatocellular iron metabolism and the association of altered iron metabolism with the initiation of acute hepatic necrosis. Administration of hepatotoxic doses (0.1 mmol/kg) of diquat to male Fischer-344 rats increased biliary iron concentrations from 6 microM to more than 15 microM. However, increases in biliary efflux of iron were not observed during the first 60 min following exposure to diquat, despite the rapid increases in biliary glutathione disulfide concentrations, which increased maximally within 40 min. Biliary efflux of iron was not altered by diquat in Sprague-Dawley rats, which are resistant to hepatic necrosis in response to diquat, despite the marked oxidant stress responses observed in these animals. Conversely, hepatotoxic doses of acetaminophen (1500 mg/kg) caused significant decreases in biliary iron efflux. The rapid decreases in biliary iron caused by acetaminophen and the delay in diquat-induced iron efflux suggested the possibility that some fraction of the biliary iron was being excreted as reversibly formed GS-Fe2+ chelates, with inhibition of export by glutathione disulfide (GSSG) in the case of diquat, or by 3-(glutathion-S-yl)-acetaminophen (GS-AAP) in the case of the acetaminophen-treated animals. However, 50-200 mg/kg doses of acetaminophen showed little effect on biliary iron excretion despite producing biliary GS-AAP conjugate concentrations almost 1000 times the 6 microM concentrations of iron, which would not appear to support the hypothesis of excretion of GS-Fe2+ chelates. The data demonstrate a significant effect of diquat on hepatic iron metabolism in Fischer-344 rats, and the possible importance of this iron redistribution to reactive oxygen-mediated cell damage in vivo is indicated by the absence of similar responses in diquat-treated Sprague-Dawley rats.

Acetaminophen↗
PubMed1994

Evidence for redox cycling of diquat in rat small intestine.

It has previously been established that acute diquat (1,1'-ethylene, 2,2'-bipyridilium) toxicity in the rat is associated with stimulation of net fluid secretion into the gastrointestinal tract. We have examined the possibility that the mechanism of diquat toxicity in the small intestine involves redox cycling of the bipyridyl leading to a disturbance of biochemical function and oxidative stress. Experiments performed in vitro showed that diquat (10 microM to 1 mM) produced an increase in activity of the pentose phosphate pathway in rat small intestinal tissue slices, suggesting that there was oxidation of NADPH even at concentrations of diquat which do not cause intestinal fluid secretion in anaesthetized rats. When the effect of diquat on pentose phosphate activity was measured in rats in situ at a dose which causes maximal fluid secretion [50 mM diquat dibromide (DQBr2)], production of 14CO2 from [1-14C]-glucose increased by 278 +/- 28% (N = 4) within 1 hr of exposure to diquat. Under these same conditions, the tissue content of NADPH in the proximal small intestine was significantly depleted, though there was no corresponding increase in NADP+ concentration. Diquat had no effect on tissue concentrations of either the reduced or oxidized forms of NAD. It is likely that NADPH oxidation at low diquat concentrations can be adequately compensated for by mechanisms within the tissue which protect against oxidative stress. However, the data also suggest that diquat-induced fluid secretion in the rat small intestine is associated with redox cycling of bipyridyl leading to depletion of NADPH.

Animals↗
PubMed1980

Liver necrosis and lipid peroxidation in the rat as the result of paraquat and diquat administration. Effect of selenium deficiency.

Paraquat and diquat facilitate formation of superoxide anion in biological systems, and lipid peroxidation has been postulated to be their mechanism of toxicity. Paraquat has been shown to be more toxic to selenium-deficient mice than to controls, presumably as the result of decreased activity of the selenoenzyme glutathione peroxidase. The present study was designed to measure lipid peroxidation and to assess toxicity in control and selenium-deficient rats given paraquat and diquat. Lipid peroxidation was measured by determining ethane production rates of intact animals; toxicity was assessed by survival and by histological and serum enzyme evidence of liver and kidney necrosis. Paraquat and diquat were both much more toxic to selenium-deficient rats than to control rats. Diquat (19.5 mumol/kg) caused rapid and massive liver and kidney necrosis and very high ethane production rates in selenium-deficient rats. The effect of paraquat (78 mumol/kg) was similar to that of diquat but was not as severe. Acutely lethal doses of paraquat (390 mumol/kg) and diquat (230 mumol/kg) in control rats caused very little ethane production and no evidence of liver necrosis. These findings suggest that paraquat and diquat exert their acute toxicity largely through lipid peroxidation in selenium-deficient rats. Selenium deficiency had no effect on superoxide dismutase activity in erythrocytes or in 105,000 g supernate of liver or kidney. Glutathione peroxidase, which represents the only well-characterized biochemical function of selenium in animals, was dissociated from the protective effect of selenium against diquat-induced lipid peroxidation and toxicity by a time-course study in which selenium-deficient rats were injected with 50 mug of selenium and later given diquat (19.5 mumol/kg). Within 10 h, the selenium injection provided significant protection against diquat-induced lipid peroxidation and mortality even though this treatment resulted in no rise in glutathione peroxidase activity of liver, kidney, lung, or plasma at 10 h. This suggests that a selenium-dependent factor in addition to glutathione peroxidase exists that protects against lipid peroxidation.

Animals↗
PubMedDate not supplied

Redox cycling and hepatotoxicity of diquat in aging male Fischer 344 rats.

The aim of this study was to determine the influence of aging on diquat-induced redox cycling in liver microsomes and diquat hepatotoxicity in rats. Diquat-stimulated production of superoxide anion radical and NADPH-cytochrome c (P-450) reductase activity were measured in liver microsomes prepared from male Fischer 344 rats at ages representing young adulthood (5-6 months), middle age (15-16 months), and old age (24-27 months). Both activities were decreased substantially (40%) in old rats. Diquat-induced liver damage was assessed 6 hr after the administration of diquat (0.1 mmol/kg, ip) on the basis of serum ALT and sorbitol dehydrogenase activities, hepatic microsomal cytochrome P-450 loss, and histological evaluation. The classical manifestations of hepatotoxicity in diquat-treated rats were as severe in old rats as in young-adult ones, despite the age-associated drop in redox cycling capacity. Diquat treatment also resulted in decreased concentrations of hepatic glutathione and ascorbic acid, increased concentrations of hepatic nonheme iron, and decreased liver weights. The changes in glutathione, nonheme iron, and liver weight were more pronounced in livers of middle-aged and old rats than in those of young-adult rats. These age-dependent differences could not be explained on the basis of plasma diquat concentrations, which were similar in the three age groups of rats. The absence of an effect of aging on the hepatotoxic effects of diquat indicates that redox cycling capacity is not limiting for the development of liver damage. Other effects of diquat were influenced by aging, but their relevancy to the hepatotoxicity is uncertain.

Aging↗
PubMed1994

Biliary excretion of lysosomal enzymes, iron, and oxidized protein in Fischer-344 and Sprague-Dawley rats and the effects of diquat and acetaminophen.

Administration of hepatotoxic doses of diquat to male Fischer-344 rats increases biliary excretion of nonheme iron, whereas comparably hepatotoxic doses of acetaminophen decrease biliary export of iron. The effects of acetaminophen and diquat on the activities in bile of representative lysosomal enzymes, beta-N-acetylglucosaminidase (beta-NAG) and beta-glucuronidase (beta-GLUC) were examined as a means of assessing the possible role of lysosomal exocytosis in the effects of these hepatotoxins on biliary excretion of iron. In pentobarbital-anesthetized male Fischer-344 rats, diquat at 0.1 mmol/kg increased the biliary export of biliary beta-NAG and beta-GLUC, in conjunction with similar increases in iron. Sprague-Dawley rats, which are resistant to diquat-induced hepatic necrosis despite showing marked oxidant stress responses, showed no increases in biliary efflux of iron, beta-NAG, or beta-GLUC in response to diquat. Conversely, acetaminophen at doses of 400 or 1500 mg/kg markedly decreased biliary concentrations and efflux rates of beta-NAG and beta-GLUC in Fischer-344 rats in parallel with decreases in biliary iron, suggesting that the hepatotoxin-induced effects on biliary iron excretion may be mediated through effects on lysosomal exocytosis. Both acetaminophen and diquat increased total protein content of bile in both strains of rats; however, the proteins excreted after administration of diquat to Fischer-344 rats showed marked increases in contents of protein carbonyls, as assayed with 2,4-dinitrophenylhydrazine, whereas biliary proteins in acetaminophen-treated animals were not more oxidized than in controls. Sprague-Dawley rats given diquat showed no increase in the biliary excretion of protein carbonyls, despite the increased excretion of glutathione disulfide observed in these animals. The significant increases in biliary excretion of protein carbonyls by the diquat-treated Fischer-344 rats suggest oxidation of cellular proteins catalyzed by chemically reactive iron chelates and the excretion of at least some of the oxidized proteins to the bile, possibly through lysosomal exocytosis. The effects of acetaminophen on biliary protein excretion do not appear to involve oxidation.

Acetaminophen↗