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S J Stohs

Publications and source records attributed to S J Stohs.

At least 73 records · Page 4Linked to original sources
PubMed1995

Protective effects of antioxidants against uraemia-induced lipid peroxidation and glutathione depletion in humans.

The effects of uraemias and antioxidant therapy for 40 days with vitamin A, vitamin C and vitamin E on blood and erythrocyte sulfhydryl (glutathione, GSH) content and on erythrocyte glutathione-S transferase (GST), glutathione reductase (GSR) and glutathione peroxidase activities were studied in six uraemic patients maintained on haemodialysis. In addition, the effect of antioxidant therapy on erythrocyte lipid peroxidation was determined, and erythrocyte haemoglobin content was measured. Uraemic patients in dialysis exhibited significant decreases in blood and erythrocyte GSH content as well as significant decreases in the activities of GST, GSR and GSH-peroxidase relative to control subjects. Furthermore, the uraemic patients had elevated erythrocyte malondialdehyde levels. Blood and erythrocyte GSH content from uraemic patients was significantly elevated after 20 days of antioxidant treatment and remained elevated thereafter throughout the remaining 20 days of the study (130% and 173%, respectively). Antioxidant therapy also produced significant increases in GSR and GSH-peroxidase activities after 20 days of treatment which remained relatively constant thereafter. No significant change in GST activity was observed. Erythrocyte malondialdehyde levels, as an index of oxidative tissue damage, exhibited a significant decrease (70%) in the patients after 40 days of antioxidant therapy. A gradual increase in erythrocyte haemoglobin content was observed following treatment of the uraemic subjects (45% at day 40). The results suggest that antioxidant therapy may protect against oxidative stress associated with uraemia.

Antioxidants↗
PubMed1995

The role of free radicals in toxicity and disease.

Free radicals are defined as atoms or molecules that contain one or more unpaired electrons. The toxicity of many xenobiotics is associated with the metabolic activation of foreign compounds to form free radicals or with the production of reactive oxygen species as superoxide anion, hydroxyl radicals or hydrogen peroxide which are responsible for the tissue damaging effects as lipid peroxidation, and DNA and protein damage. Oxidative stress associated with production of reactive oxygen species is believed to be involved not only in the toxicity of xenobiotics but also in the pathophysiology of aging, and various age-related diseases, including cataracts, atherosclerosis, neoplastic diseases, diabetes, diabetic retinopathy, chronic inflammatory diseases of the gastrointestinal tract, aging of skin, diseases associated with cartilage, Alzheimer's disease, and other neurologic disorders. The cellular sources of free radicals and reactive oxygen species, the biological targets of free radicals, and clinical conditions which are associated with free radical production and tissue damage are reviewed. In addition, potential therapeutic approaches to the prevention of free radical damage are considered. Free radical-induced injury can explain many clinical conditions.

Aging↗
PubMed1995

Chronic effects of smokeless tobacco extract on rat liver histopathology and production of HSP-90.

Tobacco consumption is a worldwide problem. The recent increase in the consumption of the smokeless tobacco products (snuff and chewing tobacco) has stimulated interest into the carcinogenic effects of these forms of tobacco. The use of smokeless tobacco products has increased in popularity as the use of cigarettes has become less socially acceptable. For most individuals the use of tobacco is a chronic process. Therefore, the effects of an aqueous extract of smokeless tobacco (STE) in rats following low-dose exposure were examined. Female Sprague-Dawley rats were treated orally with 25 mg STE/kg every other day for 90 days. In order to obtain information regarding the cytotoxicity of STE, the ultrastructural changes occurring in livers of rats following administration of STE were examined under light and electron microscopy. Electron microscopy revealed that in the perisinusoidal spaces an accumulation of indistinct filamentous material occurred following 60 days of treatment, occupying most of the sinusoids. Moreover, the lipids were in a state of disintegration. Significant increases in 90 kDa protein expression were also observed due to chronic treatment with STE. Western blot analysis using a polyclonal mouse antibody against heat shock/stress protein 90 (HSP90) confirmed that the overexpressed proteins were heat shock/stress proteins (HSPs). The HSPs are believed to serve as adaptive or survival functions involving a rapid but transient reprogramming of cellular metabolic activity to protect cells from oxidative damage.

Animals↗
PubMed1994

Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin is mediated by the aryl hydrocarbon (Ah) receptor complex.

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its bioisosteres involves binding to a specific TCDD (Aryl hydrocarbon (Ah)) receptor, interaction of this complex with chromatin, and the ultimate production of a pleiotropic response. The mechanism whereby toxic effects are produced following interaction of TCDD with the receptor complex is not known. Oxidative stress (OS) may play an important role in expression of the toxic manifestations of TCDD. TCDD has been shown to produce a dose- and time-dependent increase in superoxide anion from peritoneal lavage cells (PLC) (primarily macrophage). Therefore, to determine if TCDD-induced production of superoxide anion by PLC is mediated through the Ah receptor, congenic mice were used which differ at the Ah locus. One day after the administration of 5, 25, 50 or 125 micrograms TCDD/kg p.o. as a single dose, 1.4-, 1.7-, 4.3- and 3.5-fold increases, respectively, occurred in superoxide anion production by PLC from the TCDD-responsive C57BL/6J (bb) mice relative to control cells. However, only 125 micrograms TCDD/kg produced a significant increase in superoxide anion formation with PLC from the non-responsive C57BL/6J (dd) strain of mice (1.7-fold increase). The role of the Ah receptor was further evaluated by utilizing the TCDD-resistant DBA/2 strain of mice, two TCDD congeners and in vitro studies. The combined results indicate that TCDD produces an oxidative stress in mice as measured by production of superoxide anion, and this effect is controlled in part by the Ah receptor complex.

Animals↗
PubMed1994

The modulating effects of tumor necrosis factor alpha antibody on ricin-induced oxidative stress in mice.

Previous studies in our laboratory have shown that the protein toxin ricin induces an oxidative stress in mice, resulting in increased urinary excretion of malondialdehyde (MDA), formaldehyde (FA), and acetone (ACON). Other toxicants have been shown to induce oxidative stress by macrophage activation with subsequent release of reactive oxygen species and tumor necrosis factor alpha (TNF-alpha). Therefore, the ability of TNF-alpha antibody to modulate ricin-induced urinary carbonyl excretion as well as hepatic lipid peroxidation, glutathione depletion, and DNA single-strand breaks was assessed. Ricin-induced urinary MDA, FA, and ACON were reduced significantly in mice receiving antibody (15,000 U/kg) 2 hours before treatment with ricin (5 micrograms/kg). At 48 hours following ricin treatment, MDA, FA, and ACON concentrations in the urine of TNF antibody-treated mice decreased 25.7, 53.2, and 64.5%, respectively, relative to ricin-treated mice receiving no antibody. In addition, anti-TNF-alpha (1500 U/kg) significantly decreased hepatic lipid peroxidation and DNA single-strand breaks, induced by 5 micrograms ricin/kg, by 49.3 and 44.2%, respectively. The results suggest that macrophage activation and subsequent release of TNF-alpha are involved in ricin toxicity.

Acetone↗
PubMed1994

Quantitative determination of urinary lipid metabolites by high pressure liquid chromatography as indicators of menadione-induced in vivo lipid peroxidation.

The one- and two-electron-reduction reactions of menadione result in the generation of reactive oxygen species which are believed to mediate the cytotoxicity of this xenobiotic. The induction of lipid peroxidation in liver and isolated hepatocytes occurs in response to the menadione-mediated formation of reactive oxygen species. However, studies on the effects of menadione on the urinary excretion of lipid metabolites have not been conducted. The effect of a single oral dose of 60 mg menadione/kg to rats on the urinary excretion of the lipid metabolites malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), and acetone (ACON) has been examined over 48 h post-treatment. The urinary metabolites were identified by gas chromatography-mass spectrometry and quantitated by high pressure liquid chromatography. Time-dependent increases in the urinary excretion of the four metabolites were observed after menadione administration. Over the 48 h of the study, the menadione-induced urinary excretion of MDA, FA, ACT, and ACON increased by approximately 1.5-, 2.0-, 1.7-, and 3.2-fold, respectively, relative to control animals. The data were expressed in nmoles/kg body weight/4.5 h. The results clearly demonstrate that menadione increases the urinary excretion of four lipid metabolites. These metabolites may have widespread applicability as biomarkers of altered lipid metabolism in disease states and exposure to environmental pollutants/xenobiotics which induce enhanced lipid peroxidation. The non-invasive methods offer advantages over most other methods for assessing oxidative stress in vivo.

Animals↗
PubMed1994

Stimulation of NADPH-dependent reactive oxygen species formation and DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat peritoneal lavage cells.

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] and its congeners involves binding to a specific TCDD [Ah] receptor, interaction of this complex with chromatin, and the ultimate production of pleiotropic responses. The mechanism whereby these effects are produced following interaction of TCDD with the receptor complex is not known. Oxidative stress following the production of reactive oxygen species (ROS) may play an important role in the toxic manifestations of TCDD. Thus, the dose and time-dependent effects of TCDD on the production of superoxide anion by peritoneal lavage cells (primarily macrophages) from rats were examined. A maximum increase in superoxide anion production occurred on day 1 after treatment in rats with 50 and 125 micrograms TCDD/kg. At 6 h after a single dose of 125 micrograms TCDD/kg, a 2.4-fold increase in superoxide anion production was observed in peritoneal lavage cells from rats. A single dose of 5 micrograms TCDD/kg had no effect on superoxide anion production by peritoneal lavage cells. A significant increase in DNA single strand breaks within peritoneal lavage cells occurred at 12 h after the oral administration of 50 micrograms TCDD/kg, and a maximum increase in DNA single strand breaks was observed on days 3-5 after treatment. No DNA damage was detected at a dose of 5 micrograms TCDD/kg. No difference was observed with respect to dose and time in the composition of the peritoneal lavage cells. The results clearly indicate that the oral administration of TCDD activates peritoneal lavage cells in rats, and that the activation precedes the formation of DNA single strand breaks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Excretion of malondialdehyde, formaldehyde, acetaldehyde, acetone and methyl ethyl ketone in the urine of rats given an acute dose of malondialdehyde.

A high pressure liquid chromatographic system (HPLC) has recently been developed for the simultaneous detection of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON). We have examined the urinary excretion of these four lipid metabolites in the urine of rats following the acute oral administration of MDA (158 mg/kg body weight). During the first 12 h, increases in the urinary excretion of MDA and ACT of approximately 192- and 70-fold, respectively, were observed. The urinary excretion of both MDA and ACT decreased thereafter. An increase in FA excretion was observed only 12-24 h after MDA administration. A significant decrease in ACON relative to control values was observed 12-48 h after MDA treatment. Two new peaks were present in the HPLC chromatograms of urine samples 0-24 h after MDA administration. Both peaks were shown to be due to methyl ethyl ketone (MEK) which appears to be formed as a result of MDA metabolism. The results demonstrate that orally administered MDA is rapidly excreted in the urine, and alters the metabolism and excretion of other lipid metabolites.

Acetaldehyde↗
PubMed1994

Nephrotoxicity of gentamicin and co-trimoxazole combination in rats.

1. The nephrotoxicity of gentamicin is well known. However, little information is available regarding the combined effects of gentamicin plus co-trimoxazole (sulfamethoxazole-trimethoprim). Therefore, Wistar rats were treated daily with 100 mg/kg gentamicin or 100 mg/kg gentamicin plus 30 mg/kg trimethoprim-150 mg/kg sulfamethoxazole for 14 days. 2. Serum biochemical parameters were measured on days 0, 8 and 15, and histopathological examinations of kidneys were performed on day 15, one day following end of treatment. Gentamicin treated rats exhibited a 63% increase in blood urea nitrogen (BUN), a 124% increase in uric acid, and a 63% decrease in serum potassium levels on day 15. 3. The combination of gentamicin plus co-trimoxazole partially ameliorated these effects. With the three drug combination no change occurred in BUN, and only a 30% decrease occurred in serum potassium levels. 4. While serum creatinine levels significantly increased following gentamicin, the co-administration of co-trimoxazole resulted in a significant decrease (30%) in creatinine. Histopathological examinations of kidneys suggested a lower degree of nephrotoxicity in rats treated with gentamicin plus co-trimoxazole as compared to animals treated with gentamicin alone. 5. The results support the importance of monitoring serum biochemical parameters when treating with gentamicin or gentamicin plus co-trimoxazole.

Animals↗
PubMed1994

The effects of anti-TNF-alpha antibody and dexamethasone on TCDD-induced oxidative stress in mice.

Recent studies have implicated tumor necrosis factor alpha (TNF-alpha) in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since TNF-alpha sensitizes and activates phagocytic cells to agents that induce them to release reactive oxygen species, TNF-alpha may act as an amplifying loop in TCDD-induced oxidative stress (OS). Therefore, the effects of anti-TNF-alpha antibody (40 micrograms/mouse) and dexamethasone (2 mg/kg) treatment on TCDD-induced OS as measured by DNA single-strand breaks (SSB) in hepatic nuclei, lipid peroxidation in hepatic mitochondria and microsomes, and activation of peritoneal lavage cells (PLC) in C57BL/6J mice were studied. One day after treatment with 125 micrograms TCDD/kg, anti-TNF-alpha resulted in 70, 27, 33 and 21% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, relative to TCDD-treated mice. Dexamethasone produced 8, 32, 35 and 9% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, in TCDD-treated animals. The combination of anti-TNF-alpha and dexamethasone resulted in 67, 55, 61 and 25% decreases in the above parameters of OS, respectively. The results suggest that TNF-alpha release may play a role in sensitizing and activating phagocytic cells following treatment with TCDD, contributing to the overall OS of animals following exposure to TCDD.

Animals↗
PubMed1994

Age-related oxidative damage in Long-Evans rat retina.

The effect of age on the endogenous production of reactive oxygen species, catalase activity and lipid peroxidation in isolated rod photoreceptor outer segment membranes of Long-Evans rat retina was investigated. In rod outer segment membranes from rats at 90 days of age, the generation of reactive oxygen species was 4.0-fold higher than in membranes obtained from 23 day old animals. On the other hand, catalase activity was significantly lower in membranes from 90 day old rats as compared to those from 45 and 23 day old animals. Membrane lipid peroxidation was 2.0-fold higher in rod outer segments from 90 day old rats as compared to those from 23 days old animals. An age-dependent increase in membrane microviscosity in rod outer segments was also observed indicating a decrease in membrane fluidity during aging. The results indicate that the intramural generation of reactive oxygen species and membrane lipid peroxidation increases with age in rod photoreceptor outer segments from Long-Evans rat retina.

Aging↗
PubMed1994

Smokeless tobacco induced increases in hepatic lipid peroxidation, DNA damage and excretion of urinary lipid metabolites.

The possible role of reactive oxygen species in the toxicity of smokeless tobacco (ST) was explored. The effects of an aqueous smokeless tobacco extract (STE) at doses of 125, 250 and 500 mg STE/kg in rats on the induction of hepatic mitochondrial and microsomal lipid peroxidation and the incidence of hepatic nuclear DNA damage 24 hours post treatment were examined. Dose-dependent increases of 1.8, 2.3 and 4.4-fold in mitochondrial and 1.5, 2.1 and 3.6-fold in microsomal lipid peroxidation occurred at 125, 250 and 500 mg STE/kg, respectively, relative to control values. At these same three doses of STE, 1.3, 1.4 and 2.7-fold increases in hepatic DNA single-strand breaks occurred relative to control values. STE administration also resulted in significant increases in excretion of urinary metabolites. Urinary excretion of the four lipid metabolites malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON) was monitored by HPLC for 72 hours after treatment of rats with 125 and 250 mg STE/kg. Increases occurred in the excretion of the four lipid metabolites at every dose and time point with maximum increases in the excretion of all lipid metabolites being observed between 12 and 24 hours post treatment. The results suggest the involvement of an oxidative stress in the toxicity of STE.

Acetone↗
PubMed1993

Effects of carbon tetrachloride, menadione, and paraquat on the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone in rats.

Excretions of the lipid peroxidation products, formaldehyde (FA), acetaldehyde (ACT), malondialdehyde (MDA), and acetone (ACON), were simultaneously identified and quantitated in the urine of female Sprague-Dawley rats by gas chromatography-mass spectroscopy (GC-MS) and high pressure liquid chromatography (HPLC) following the acute administration of carbon tetrachloride, a model alkylating agent that does not induce glutathione depletion, and the redox cycling compounds paraquat and menadione. All three xenobiotics are well-known inducers of oxidative stress. Oxidative stress was induced by oral administration of single doses of 2.5 mL of carbon tetrachloride/kg, 60 mg menadione/kg, and 75 mg paraquat/kg. These doses are approximately 50% of the LD50's for the three xenobiotics. Urinary excretion of FA, ACT, MDA, and ACON increased relative to control animals following treatment with all xenobiotics. Over the 48 hours of the study, the greatest increases in the excretion of MDA, FA, ACT, and ACON occurred after paraquat administration, with increases of approximately 2.7-, 2.6-, 4.3-, and 11.0-fold, respectively. This technique may have wide-spread applicability as an effective biomarker for investigating altered lipid metabolism in disease states and exposure to environmental pollutants/xenobiotics.

Acetaldehyde↗
PubMed1993

Time-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on serum and urine levels of malondialdehyde, formaldehyde, acetaldehyde, and acetone in rats.

The ability of TCDD to produce lipid mobilization and alter lipid metabolism is well known. Previous studies have indicated that TCDD induces an oxidative stress and enhances lipid peroxidation. However, the products resulting from altered lipid metabolism in response to TCDD have not been studied. We have examined the time-dependent changes in serum and urine levels of malondialdehyde, formaldehyde, acetaldehyde, and acetone in response to a single oral 50 micrograms/kg dose of TCDD in rats. The changes in these four metabolic products were quantitated by high-pressure liquid chromatography (HPLC). The effects of TCDD were compared in ad libitum-fed control animals and pair-fed animals. Serum and urine levels of the four metabolites were assayed on Days 0, 3, 6, 9, and 12. Following TCDD administration, significant increases in the four metabolites present in serum and urine were observed at all time points. For example, on Day 6 post-treatment malondialdehyde, formaldehyde, acetaldehyde, and acetone increased approximately 1.8-, 1.4-, 2.0-, and 3.0-fold in serum, respectively, and 1.3-, 1.4-, 1.6-, and 2.0-fold in urine, respectively, relative to pair-fed control animals. Increases in the serum and urine levels of the four metabolites were significantly greater for TCDD animals than for pair-fed control animals at most time points. When the serum levels of malondialdehyde as determined by HPLC were compared with the results obtained by the thiobarbituric acid (TBA) colorimetric method, similar time courses were observed although higher results were obtained for the less specific TBA method. The results clearly demonstrate that TCDD causes markedly elevated serum and urine levels of four specific products associated with lipid metabolism.

Acetaldehyde↗
PubMed1993

Comparative studies on lipid peroxidation and DNA-single strand breaks induced by lindane, DDT, chlordane and endrin in rats.

1. A variety of structurally dissimilar polyhalogenated cyclic hydrocarbons produce similar toxic effects. The molecular mechanisms involved in the production of these toxic manifestations is not known. 2. We have proposed that reactive oxygen species may be involved, and have therefore examined the time-dependent effects of lindane (30 mg/kg), DDT (40 mg/kg), chlordane (120 mg/kg), and endrin (4.5 mg/kg) on the production of hepatic mitochondrial and microsomal lipid peroxidation and DNA single strand breaks, two indices of oxidative stress. 3. All four xenobiotics resulted in significant increases in hepatic lipid peroxidation and DNA damage. Earliest (6 hr) increases in both lipid peroxidation and DNA damage were observed following lindane administration. Time-dependent increases in both parameters were observed following endrin administration. 4. Maximum increases in DNA single strand breaks of 2.8- and 2.5-fold were observed 12 hr after DDT and chlordane administration, respectively, while a 4.4-fold increase was observed 24 hr after endrin administration. 5. The results demonstrate that the four structurally dissimilar polyhalogenated hydrocarbons produce oxidative tissue damage which may contribute to the toxic manifestations of these xenobiotics, and exhibit different toxicokinetic properties.

Animals↗
PubMed1993

Comparative effects of endrin on hepatic lipid peroxidation and DNA damage, and nitric oxide production by peritoneal macrophages from C57BL/6J and DBA/2 mice.

1. Endrin is a polyhalogenated cyclic hydrocarbon which produces hepatic and neurologic toxicity. In order to further assess the mechanism of toxicity of endrin, the dose-dependent effects of endrin on hepatic lipid peroxidation and DNA damage, and nitric oxide (NO) production by peritoneal exudate cells (primarily macrophages) were investigated in C57BL/6J and DBA/2 mice which vary at the Ah receptor genetic locus. C57BL/6J mice are dioxin-responsive, while DBA/2 mice are dioxin-insensitive. 2. Mice of both strains were treated with 0, 1, 2 or 4 mg endrin kg-1 as a single oral dose in corn oil, and the animals were killed 24 hr post-treatment. At doses of 1, 2 and 4 mg endrin kg-1 in C57BL/6J mice, hepatic mitochondrial lipid peroxidation increased 1.2-, 2.2- and 3.2-fold, respectively, and 1.8-, 2.3- and 3.5-fold with microsomes, respectively. At these same doses in DBA/2 mice, hepatic mitochondrial lipid peroxidation increased 1.3-, 2.0- and 2.6-fold, respectively, and 1.5-, 1.9- and 2.5-fold with microsomes, respectively. 3. Increases of 2.3-, 2.4- and 4.9-fold were observed in hepatic DNA damage (elution constants) in C57BL/6J mice at doses of 1, 2 and 4 mg endrin kg-1, respectively, while at these same three doses, increases of 1.9-, 2.1- and 2.3-fold were observed for DBA/2 mice, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗