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S J Stohs

Publications and source records attributed to S J Stohs.

At least 91 records · Page 5Linked to original sources
PubMed1993

Production of reactive oxygen species by peritoneal macrophages and hepatic mitochondria and microsomes from endrin-treated rats.

Recent studies have shown that the administration of endrin to rodents induces lipid peroxidation in various tissues and decreases glutathione content. These results suggest that endrin produces reactive oxygen species and/or free radicals. We have therefore examined the effect of endrin (4.5 mg/kg) on the production of reactive oxygen species by peritoneal macrophages and hepatic mitochondria and microsomes in rats. The effects of endrin on hepatic mitochondrial and microsomal lipid peroxidation and membrane fluidity as well as the incidence of hepatic nuclear DNA damage were also examined. Twenty-four hours after endrin administration, significant increases in the production of chemiluminescence by the three tissue fractions were observed. Furthermore, peritoneal macrophages from endrin-treated animals resulted in 3.0- and 2.8-fold increases in cytochrome c and iodonitrotetrazolium (INT) reduction, indicating enhanced production of superoxide anion. Endrin administration also resulted in significant increases in lipid peroxidation of mitochondrial and microsomal membranes as well as decreases in the fluidity of these two membranous fractions. A significant increase in hepatic nuclear DNA single-strand breaks also occurred in response to endrin administration. The results indicate that macrophage, mitochondria, and microsomes produce reactive oxygen species following endrin administration, and these reactive oxygen species may contribute to the toxic manifestations of endrin.

Animals↗
PubMed1993

Protective effects of antioxidants against endrin-induced hepatic lipid peroxidation, DNA damage, and excretion of urinary lipid metabolites.

Oxidative stress is believed to play a pivotal role in endrin-induced hepatic and neurologic toxicity. Therefore, the effects of the antioxidants vitamin E succinate and ellagic acid have been examined on hepatic lipid peroxidation, DNA single-strand breaks (SSB), and the urinary excretion of lipid metabolites following an acute oral dose of 4.5 mg endrin/kg. Groups of rats were pretreated with 100 mg/kg vitamin E succinate for 3 d followed by 40 mg/kg on day 4, or 6.0 mg ellagic acid/kg for 3 d p.o. followed by 3.0 mg/kg on day 4 or the vehicle. Endrin was administered p.o. on day 4 2 hr after treatment with the antioxidant. All animals were killed 24 h after endrin administration. Vitamin E succinate pretreatment decreased the endrin-induced increase in hepatic mitochondrial and microsomal lipid peroxidation by approximately 60% and 40%, respectively. Ellagic acid pretreatment reduced the endrin-induced increased in mitochondrial and microsomal lipid peroxidation by approximately 76 and 79%, respectively. Both vitamin E succinate and ellagic acid alone produced small but nonsignificant decreases in hepatic mitochondrial and microsomal lipid peroxidation. A 3.3-fold increase in the incidence of hepatic nuclear DNA single-strand breaks was observed 24 h after endrin administration. Pretreatment of rats with vitamin E succinate, vitamin E, and ellagic acid decreased endrin-induced DNA-SSB by approximately 47%, 22%, and 21%, respectively. Pretreatment of rats with vitamin E succinate decreased the endrin-induced increase in the urinary excretion of malondialdehyde, acetaldehyde, formaldehyde, and acetone by approximately 68, 65, 70, and 55%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1993

In vitro induction of reactive oxygen species by 2,3,7,8-tetrachlorodibenzo-p-dioxin, endrin, and lindane in rat peritoneal macrophages, and hepatic mitochondria and microsomes.

Hepatic mitochondria and microsomes as well as peritoneal macrophages from female Sprague-Dawley rats were incubated for up to 30 min at 37 degrees C in the presence of 0-200 ng/ml 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), endrin (1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4 alpha,5,6,7,8,8 alpha-octahydroendo, endo-1,4:5,8-dimethanonaphthalene), and lindane (hexachlorocyclohexane). Production of reactive oxygen species was determined by chemiluminescence and cytochrome c reduction, while potential tissue damage was assessed by alterations in membrane fluidity. Chemiluminescence, a sensitive but nonspecific measure of free radical generation, increased 40-70% when macrophages (3 x 10(6) cells/ml), mitochondria and microsomes (1 mg/ml) were incubated with the three polyhalogenated cyclic hydrocarbons (PCH). Maximum increases in chemiluminescence occurred within 5-10 min of incubation and persisted for over 30 min. The cytochrome c reduction assay is most specific for superoxide anion production. When hepatic mitochondria were incubated with endrin and lindane for 15 min at 100 ng/ml, increases in cytochrome c reduction of 6.5- and 7.5-fold occurred, respectively, while when microsomes were incubated with these same two PCH, increases in cytochrome c reduction of 8.6- and 11.6-fold occurred, respectively. When mitochondria, microsomes, and macrophages were incubated with TCDD under identical conditions, small increases in superoxide anion production were detected. Changes in microsomal membrane fluidity were determined spectrofluorometrically following incubation with the three PCH using diphenyl-1,3,5-hexatriene as the fluorescent probe. TCDD, endrin, and lindane enhanced microsomal membrane apparent microviscosity by 2.3-, 2.1-, and 2.5-fold, respectively, indicating a significant decrease in membrane fluidity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Carbon-tetrachloride-induced urinary excretion of formaldehyde, malondialdehyde, acetaldehyde and acetone in rats.

Previous studies have demonstrated that the hepatotoxin carbon tetrachloride rapidly promotes lipid peroxidation and inhibits microsomal calcium sequestration, microsomal glucose-6-phosphatase activity and cytochrome P-450. Due to its profound effects on lipid peroxidation, we have examined the oral administration of 2.5 ml/kg carbon tetrachloride on the urinary excretion of the lipid metabolites formaldehyde, malondialdehyde, acetaldehyde and acetone. Urine samples were collected up to 48 h after treatment. The urinary metabolites were identified and quantitated by gas chromatography-mass spectrometry and high-pressure liquid chromatography. Time-dependent increases in the urinary excretion of the four metabolites were observed after carbon tetrachloride administration. At 48 h after treatment, the increases in the excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone were approximately 55, 78, 57 and 268%, respectively, relative to control values. The data were expressed in nanomoles per kilogram body weight per 4.5 h. The results clearly demonstrate that carbon tetrachloride increases the urinary excretion of four lipid metabolites which may serve as noninvasive biomarkers of xenobiotic-induced lipid peroxidation.

Acetaldehyde↗
PubMed1993

Excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone in the urine of rats following acute and chronic administration of ethanol.

Recent studies have shown that xenobiotics which induce oxidative stress result in an increased production and excretion of acetaldehyde (ACT), formaldehyde (FA), acetone (ACON) and malondialdehyde (MDA) in the urine of rats. We have therefore examined the effect of acute and chronic ethanol administration on the excretion of these four lipid metabolites in female Sprague-Dawley rats. Urine samples were collected over dry ice for 6 hr time periods. Aliquots of urine were derivatized with 2,4-dinitrophenylhydrazine HCl, and extracted with n-pentane. High pressure lipid chromatogrpahy (HPLC) was used to quantitate and the hydrazones of the four lipid metabolite products. Following a single, oral, acute dose of 5 g ethanol/kg, urinary excretion of ACT increased approximately 5.8-fold from 6 to 12 hr posttreatment, and decreased thereafter. FA excretion decreased by approximately 50% from 0 to 12 hr, returned to control values in the 18-24 hr urine samples, and was 1.3-fold greater than control values at 42-48 hr. ACON increased 3.1-fold over control values from 0 to 30 hr and remained elevated throughout the remaining 18 hr of the study. The excretion of MDA increased approximately 1.5-fold from 18 to 36 hr, then remained constant through the 48 hr time point. In a separate series of experiments, a chronic oral dose of 0.5 g ethanol/kg was administered to rats for 10 consecutive days and the urinary excretion of the lipid metabolites MDA, FA, ACT and ACON was examined for 11 days, beginning with the first day of ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1992

Excretion of formaldehyde, malondialdehyde, acetaldehyde and acetone in the urine of rats in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, paraquat, endrin and carbon tetrachloride.

Formaldehyde (FA), acetaldehyde (ACT), malondialdehyde (MDA) and acetone (ACON) were simultaneously identified in urine, and their excretion quantitated in response to chemically induced oxidative stress. Urine samples of female Sprague-Dawley rats were collected over dry ice and derivatized with 2,4-dinitrophenylhydrazine. The hydrazones of the four lipid metabolic products were quantitated by high-performance liquid chromatography on a Waters 10-microns mu-Bondapak C18 column. The identities of FA, ACT, MDA and ACON in urine were confirmed by gas chromatography-mass spectrometry. An oxidative stress was induced by orally administering 100 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin, 75 mg/kg paraquat, 6 mg/kg endrin or 2.5 ml/kg carbon tetrachloride to rats. Urinary excretion of FA, ACT, MDA and ACON increased relative to control animals 24 h after treatment with all xenobiotics. The system has wide-spread applicability to the investigation of altered lipid metabolism in disease states and exposure to environmental pollutants.

Acetaldehyde↗
PubMed1992

Effect of endrin on the hepatic distribution of iron and calcium in female Sprague-Dawley rats.

The distribution of iron and calcium in hepatic subcellular fractions of female rats treated with endrin (1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4 alpha,5,6,7,8,8 alpha- octahydroendo,endo-1,4:5,8-dimethanonaphthalene) was determined. Endrin in corn oil was administered orally to rats in single doses of 3, 4.5, or 6 mg/kg, and the animals were killed at 0, 12, 24, 48, or 72 hr post-treatment. Iron and calcium were determined by atomic absorption spectroscopy. The administration of endrin increased the iron content of mitochondria and decreased the iron content of microsomes and nuclei. Significant increases occurred in the calcium content of mitochondria, microsomes, and nuclei. Thus, the results indicate that with respect to the subcellular distribution of iron and calcium, endrin produces differential effects. Vitamin E succinate administration partially prevented the endrin-induced hepatic alterations in iron and calcium homeostasis. Endrin also produced dose- and time-dependent increases in the liver and spleen weight/body weight ratios, while decreasing the thymus weight/body weight ratios. The altered distribution of calcium and iron may contribute to the broad range of effects of endrin.

Analysis of Variance↗
PubMed1992

Endrin-induced increases in hepatic lipid peroxidation, membrane microviscosity, and DNA damage in rats.

Endrin is a polyhalogenated cyclic hydrocarbon pesticide which produces hepatic and neurologic toxicity. Previous studies have indicated that endrin induces hepatic lipid peroxidation. In order to further assess the possible role of lipid peroxidation in the toxicity of endrin, the dose- and time-dependent effects of endrin on hepatic lipid peroxidation, membrane microviscosity and DNA damage in rats were examined. Rats were treated with 0, 3.0, 4.5, or 6.0 mg endrin/kg as a single oral dose in corn oil, and the animals were killed 0, 12, 24, 48, or 72 h post-treatment. Dose-dependent increases in hepatic mitochondrial and microsomal lipid peroxidation and microviscosity as well as nuclear DNA single strand breaks were observed as early as 12 h post-treatment. Maximum increases in these three parameters occurred 24 h after endrin administration at all three doses. While the incidence in DNA damage decreased with time after 24 h, the incidence of lipid peroxidation and microviscosity of microsomal and mitochondrial membranes remained relatively constant. Dose- and time-dependent increases in liver and spleen weight/body weight ratios with decreases in thymus weight/body weight ratios were observed. The data indicate that endrin administration induces hepatic lipid peroxidation which may be responsible for the increased membrane microviscosity as a result of membrane damage as well as enhanced DNA damage.

Analysis of Variance↗
PubMed1992

An assessment of potential chemoprotectant activity against ricin toxicity by mechanism based glycosidase inhibitors in macrophage J744A.1 cell cultures.

The abilities of potential chemoprotectants to inhibit cytotoxicity of ricin have been determined in vitro, using the macrophage cell line J744A.1. Six compounds were tested: alpha- and beta-galactopyranosylamine; N-bromoacetyl-alpha-D-galactopyranosylamine; N-bromoacetyl-beta-D-galactopyranosylamine; N-bromoacetylglucopyranosylamine; and N-bromoacetylmannopyranosylamine. Of the six compounds which were tested, only N-bromoacetyl-alpha-D-galactopyranosylamine and N-bromoacetyl-beta-D-galactopyranosylamine exhibited significant activity against ricin toxicity, as indicated by the release of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST). The alpha-isomer provided greater protection against ricin toxicity and also exhibited less inherent cytotoxicity in the absence of ricin, as compared to the beta-isomer. Neither the alpha- and beta-galactopyranosylamines nor the glucose and mannose analogs were promising as potential chemoprotectants.

Aspartate Aminotransferases↗
PubMed1992

Ricin-induced hepatic lipid peroxidation, glutathione depletion, and DNA single-strand breaks in mice.

The ability of ricin, the glycoprotein toxin from the castor bean (Ricinus communis), to stimulate oxidative stress was investigated. Following the i.p. administration of 25 micrograms ricin/kg or the vehicle to female CF-1 mice, the effects of ricin on hepatic lipid peroxidation, nonprotein sulfhydryl (reduced glutathione) content and DNA single-strand breaks were determined at 0, 12, 24, 36, 48 and 72 hr post-treatment. Hepatic lipid peroxidation significantly increased 3.4-, 3.8-, and 3.0-fold relative to control values at 24, 36, and 48 hr post-treatment, respectively. Hepatic nonprotein sulfhydryl concentrations decreased significantly to approximately 51%, 61% and 65% of control values, at 24, 36, and 48 hr, respectively. The incidence of hepatic DNA single-strand breaks increased by 2.9-, 2.8-, and 2.4-fold relative to the zero time values at 24, 36, and 48 hr after treatment with ricin, respectively. No significant differences were observed in either lipid peroxidation or nonprotein sulfhydryl concentrations at 12 or 27 hr post-treatment. Decreases in liver and intestinal weight to body weight ratios were observed in ricin-treated animals, while no changes were observed in spleen and kidney weight to body weight ratios. These results indicate that in the liver of mice, ricin induces an oxidative stress which is maximal at approximately 36 hr post-treatment.

Animals↗
PubMed1992

Endrin-induced urinary excretion of formaldehyde, acetaldehyde, malondialdehyde and acetone in rats.

Previous studies have shown that endrin induces an oxidative stress in rats as demonstrated by an increase in hepatic lipid peroxidation, a decrease in glutathione content and a decrease in the activity in selenium-dependent glutathione peroxidase. We have therefore examined the effects of orally administering 1.5, 3.0, 4.5 and 6.0 mg endrin/kg on the urinary excretion of the lipid metabolites formaldehyde, malondialdehyde, acetaldehyde and acetone. The simultaneous determination of these four lipid metabolites may be a useful biomarker for assessing exposure to xenobiotics which induce an oxidative stress and enhanced lipid peroxidation. Urine samples were collected up to 72 h post-treatment. The identities of the lipid metabolites were confirmed by gas chromatography-mass spectroscopy, while the 2,4-dinitrophenylhydrazine derivatives of these metabolic products were quantitated by high pressure liquid chromatography. Maximum increases in the excretion of the four lipid metabolites occurred at approx. 24 h post-treatment at all doses with no significant increases in excretion occurring thereafter. The maximum increases in excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone were approx. 160%, 93%, 121% and 162%, respectively, relative to control values. Seventy-two hours after endrin administration, the liver weight/body weight and spleen weight/body weight ratios significantly increased while the thymus weight/body weight ratio markedly decreased. The results demonstrate that endrin induces dose- and time-dependent alterations in lipid metabolism with the enhanced excretion of specific metabolic products in the urine.

Acetaldehyde↗
PubMed1992

Endrin-induced production of nitric oxide by rat peritoneal macrophages.

The effect of oral endrin administration to rats on the production of nitric oxide (NO) by peritoneal macrophages was investigated. Nitric oxide formation was measured as nitrite. Endrin (4.5 mg/kg) enhanced the secretion of NO by approx. 300%. The effect of endrin on NO formation was both dose- and time-dependent. Ellagic acid, which has been shown to be a potent antioxidant, inhibited the elevation of NO production induced by endrin. These results suggest that the toxicity of endrin may at least in part be due to the production of an oxidative stress.

Administration, Oral↗
PubMed1992

Glutathione monoethyl ester moderates mercuric chloride-induced acute renal failure.

Glutathione (GSH)-dependent reactions are an important cellular defense against ischemic or oxidative injury, although their role in toxin-induced renal cellular injury is less clear. Because of the known sulfhydryl reactivity of mercury (M), we hypothesized that GSH could modify mercuric chloride (MC)-induced acute renal failure (ARF). Therefore, we evaluated the effects of glutathione monoethyl ester (GE), which produces high intrarenal levels of GSH, on the nephrotoxicity of MC. GE treatment in normal rats did not alter their creatinine clearance (CCr), fractional sodium (CNa/CCr) or lysozyme (CLy/CCr) excretion, but histologically resulted in prominent proximal tubular vacuolization. GE pretreatment in rats with MC-induced ARF resulted in partial preservation of their CCr, CNa/CCr and CLy/CCr. Renal histology also demonstrated a reduction in tubular necrosis. M content in the renal cortex 3 following MC was lower in the MC + GE group, but levels were higher in the liver and inner stripe/inner medulla as compared to animals receiving MC alone. No differences were seen in the outer stripe at 3 h or in any of the tissues 24 h following MC injection. Thus, GE moderated MC-induced ARF, likely by providing a large intracellular sulfhydryl pool and thereby reducing M reactivity with endogenous cellular proteins and enzymes.

Acute Kidney Injury↗
PubMed1992

Role of glutathione metabolism in the reduction of proteinuria by dimethylthiourea in adriamycin nephrosis.

Glutathione (GSH) metabolism, a tissue detoxification pathway, was evaluated in rats with adriamycin nephrosis (AN) treated with dimethylthiourea (DMTU), a free radical scavenger. After 7 days of DMTU, a significant reduction in proteinuria occurred as compared to AN controls (62.4 +/- 13.3 vs. 155.0 +/- 24.0 mg/24 h). A significant increase in renal cortical GSH content as well as glutathione peroxidase (GP) and transferase (GT) activities occurred in DMTU-treated rats as compared to controls. Glutathione monoethyl ester (GME) administration alone reduced proteinuria by 21% in AN, which was not significant despite a large increase in the renal GSH content, however, GP and GT activities were not increased by GME. We conclude that DMTU ameliorates glomerular injury in AN by stimulating GSH metabolism.

Animals↗
PubMed1991

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hepatic estrogen and glucocorticoid receptors in congenic strains of Ah responsive and Ah nonresponsive C57BL/6J mice.

The present study examines the role of the Ah receptor in the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the binding capacity of the hepatic glucocorticoid (GC) and estrogen (E) receptors in female congenic C57BL/6J mice differing only at the Ah (aromatic hydrocarbon responsiveness) locus. The Ah locus is thought to encode the Ah receptor, which regulates the effects of TCDD and related compounds on cytochrome P450IA1 and appears to mediate most of the toxic effects of TCDD. The differences between Ah responsive (Ahb/b) and nonresponsive (Ahd/d) mice appear to reflect differences in the affinity of the Ah receptor in the two strains for ligands such as TCDD. Administration of a single oral dose of TCDD (30 micrograms/kg) to Ahb/b mice produced approximately a 30% decrease in the maximum binding capacities of both the hepatic GC and E receptors, as well as 50-fold induction of a P450IA1-mediated enzymatic activity, ethoxyresorufin-O-deethylase (EROD). Tyrosine aminotransferase (TAT) activity, which is mediated by the GC receptor, was also decreased approximately 30% by TCDD. Dose-response curves indicated that Ah responsive mice are 10-fold more sensitive to induction of EROD than Ah nonresponsive mice (ED50 1.6 vs 15 micrograms/kg), as would be expected for an effect mediated by the Ah receptor. Dose-response curves also indicated that there was a statistical difference in the responsiveness of the hepatic E receptor to TCDD in the two congenic strains of mice (p less than 0.01). Surprisingly, no significant differences in the dose-response curves for the effect of TCDD on hepatic GC receptor binding or TAT activity were observed in the two strains of mice in two separate experiments. These results indicate that the Ah receptor regulates the effects of TCDD on the binding of estrogen to the hepatic estrogen receptor, but suggest that the decrease in the binding capacity of the hepatic GC receptor does not appear to be mediated directly by the Ah locus.

Animals↗
PubMed1991

Evaluation of potential chemoprotectants against microcystin-LR hepatotoxicity in mice.

Microcystin-LR (MCLR) is a potent cyclic heptapeptide hepatotoxin produced by the blue-green algae, Microcystis aeruginosa. Toxic blooms of this cyanobacteria have been reported throughout the temperate world. In spite of the potential economic loss and health hazard posed by this toxin, few studies on the development of an antidote have been conducted. Thus, a number of biologically active compounds were tested in mice for effectiveness in preventing the toxicity of a lethal dose of MCLR (100 micrograms kg-1). Efficacy was evaluated based upon the percentage of surviving mice, time to death and serum lactate dehydrogenase activity 45 min after treatment with the toxin. The biologically active compounds were separated into groups based upon proposed mechanisms of action. Enzyme induction by phenobarbital but not by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in partial protection against toxicity. Calcium channel blockers, free-radical scavengers and water-soluble antioxidants produced little protection against toxicity. The membrane-active antioxidants vitamin E and silymarin, as well as glutathione and the monoethyl ester of glutathione, produced significant protection from lethality. Rifampin and cyclosporin-A, both immunosuppressive and membrane-active agents, which also block the bile acid uptake system of hepatocytes, produced complete protection from the toxicity of MCLR. Thus, lipophilic antioxidants provide partial protection against MCLR toxicity while cyclosporin-A and rifampin are highly effective and potentially useful antidotes. The toxicity of MCLR may depend upon stimulation of the immune system and may be mediated by membrane alterations.

Animals↗
PubMed1991

The possible role of phospholipase A2 in hepatic microsomal lipid peroxidation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats.

The induction of lipid peroxidation in hepatic microsomes of rodents treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is well documented. The potential mechanisms involved in TCDD-induced microsomal lipid peroxidation were investigated, using selected inhibitors and free radical scavengers in vitro. Rats were treated with 40 micrograms TCDD/kg orally as a single dose. Inhibitors of phospholipase A2, including a variety of phenothiazines, dibucaine, imipramine, and verapamil, inhibited in vitro microsomal lipid peroxidation in response to TCDD administration. In addition, the lipoxygenase inhibitor quercetin, and the hydrogen peroxide scavenger aminopyrine inhibited lipid peroxidation with microsomes from TCDD-treated rats. The singlet oxygen scavenger beta-carotene, the cytochrome P-450 substrate benzphetamine, and the cyclooxygenase inhibitor indomethacin produced moderate enhancement of hepatic microsomal lipid peroxidation. The results suggest that activation of phospholipase A2 may play a critical role in the metabolic events associated with hepatotoxicity and ultimate cell death produced by TCDD. The results also support the involvement of hydrogen peroxide in TCDD-induced microsomal lipid peroxidation.

Aminopyrine↗