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The Korean Society of Toxicology
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Volume 11, Issue 2 - Dec 1995
Volume 11, Issue 1 - Jun 1995
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Effects of Tumor Necrosis Factor Alpha on Growth and Tube Formation of Bovine Vascular Endothelial Cells in vitro
Yoon, Duc- ; Hwa-Joong ;
Toxicological Research, volume 11, issue 2, 1995, Pages 169~173
The effects of tumor necrosis factor alpha
on growth and tubular formation of bovine aortic endothelial cells were examined using an in vitro angiogenesis model system. The growth of endothelial cells was enhanced in a dose-dependent manner when the cells were cultured with
for 3 days, but
, at the concentration of 1 nM or higher, produced a growth inhibition of endothelial cells when the cells were cultured for 8 days. The endothelial cells incubated with
for 48-h exhibited a typical morphologic change. Then, they showed a fibroblastoid organization of overlapping, elongated, and spindle-shaped cells.
, at the concentration of O. 1 nM or higher, inhibited the tubular formation of vascular endothelial cells in an in vitro anglogenesis model using a 3-dimensional culture system.
Growth-Inhibiting Effect of Bufadienolides on Cultured Vascular Endothelial Cells
Lee, Duck-Yoon ; Yoon, Hwa-Joong ;
Toxicological Research, volume 11, issue 2, 1995, Pages 175~180
We found that bufalln, one of the prominent components of the bufadlenolides in the Chinese medicine chan'su, has the potent inhibitory effects on growth and proliferation of the cultured bovine aortlc endothelial (BAE) and human umbilical vein endothelial (HUVE) cells. All naturally-occuring bufadienolides used in this study inhibited the cell growth in a dose-dependent manner. Particularly, bufalin among the bufadienolides showed the strongest inhibitory activity for the cell growth. The order of growth inhibition by bufadienolides on BAE cells was as follows: bufalin > gamabufotalln > bufotalln > cinobufagin > cinobufotalin > resibufogenin. The
values (50% inhibition of cell growth) of bufalin as determined by XTT assay were the range of 1-10 nM in BAE and HUVE cells. Bufalin exhibited a higher sensitivity towards cultured bovine aortic endothelial cells than human umbilical vein endothelial cells.
Effect of Biphenyl Dimethyl Dicarboxylate on Chemical-Induced Hepatotoxicity
Kim, Sun-Hyung ; Cho, Young-Jin ; Bae, Yong-Jin ; Lee, Kweon-Haeng ; Lee, Sang-Bok ;
Toxicological Research, volume 11, issue 2, 1995, Pages 181~185
To know the mechanism of biphenyl dimethyl dicarboxylate (DDB) in the protection of chemically induced hepatotoxicity, the activity of glutamic pyruvic tran.saminase (GPT) and the level of lipid peroxidation metabolite (malondialdehyde, MDA) and ATP content in hepatocytes were determined in serum and primarily cultured hepatocytes. For in vibo study, rats were pretreated with DDB (300 mg/ kg, p.o.)for 7 days. DDB pretreatment efficiently reduced the elevation of serum GPT activity induced by carbon tetrachloride (1.6 ml/kg, s.c.) and acetaminophen administration (1500 mg/kg, i.p.). In ex vivo study, hepatocytes were isolated from the rats pretreated with DDB (300 mg/kg, p.o.)for 7 days and cultured for 12 hrs before inducing cytotoxicity with chemicals. The MDA formation and the GPT release induced by adriamycin
were markedly decreased in the hepatocytes from the rats pretreated with DDB as compared to vehicle only. However, DDB pretreatment did not prevent the decrease of ATP contents of hepatocytes induced by cisplatin and adriamycin. In in vitro experiment, DDB was pretreated in primary cultured hepatocytes for 3 days. DDB enhanced the decreases of ATP contents induced by cisplatin and adriamycln. These results suggest that DDB may protect the hepatocytes from injury induced by hepatotoxlcants through inhibiting the lipid peroxidation.
Neuronal Cytotoxicity of Oxygen Radical in Newborn Mouse Forebrain Culture
Lim, Kye-Taek ; Park, Seung-Taeck ; Choi, Min-Kyu ; Chung, Yeun-Tai ;
Toxicological Research, volume 11, issue 2, 1995, Pages 187~192
The cytotoxic effects of hydrogen peroxide and neuroprotective effects of a variety of agents were investigated in newborn mouse forebrain tissue culture. In our experiments, oxygen radical was generated enzymatically by glucose oxidase and the values were expressed as a percentage of number of living cells by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cytotoxicity of oxygen radicals was prevented by catalase and (N, N, N', N', -tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), but N-tetra-ot-butyl-phenylnitrone (PBN), and deferoxamine (DFX), failed to show protective effects against oxygen radicals. Antagonists of the N-methyl-D-aspartate (NMDA) receptor, D-2-amino-5-phosphonovaleric acid (APV), 7-chlorokynurenic acid (CKA), and MK801 (a non-competitive NMDA antagonist) were also not effective in blocking neurotoxicity induced by glucose oxidase generated oxygen radicals.
Toxic Activity of Ricin and RCA from Ricinus communis on Leukemia Cells and ICR Mice
Toxicological Research, volume 11, issue 2, 1995, Pages 193~197
Antibody-toxin conjugates, termed immunotoxins, are currently being evaluated as potential new anticancer agents and one of the most extensively studied toxins for construction of immunotoxin is ricin which exists in the seeds of castor bean, Ricinus communis. Another toxic lectin from castor bean is RCA (Ricinus communis agglutinin). Both toxins are very homologous. We reported the puriffcation procedure and biological properties of ricin from the Korean castor bean in another place and here we report those of RCA. The purified RCA shows three bands on denatured SDS PAGE while ricin shows two bands. On cultured
cells ricin and RCA both inhibit the multiplication of cells extensively.
of ricin shows 73% of inhibition rate at day 4 compared to 68% in same condition of RCA. The inhibition of multiplication of cells are directly proportional to the concentration of toxins and the incubation period. In every case ricin was more toxic than RCA. The
dose of ricin on ICR mice was 60 ng at day 3 but that of RCA was
Effects of Extracellular Calcium and Starvation on Biochemical Indices of the Rat Hepatocytes
Kim, Ki-Sung ;
Toxicological Research, volume 11, issue 2, 1995, Pages 199~203
The focus of this study was to investigate that cellular parameters and glucose uptake might be altered by extracellular calcium and starvation. Addition of 1 mM
to hepatocytes (equalling to the free calcium concentration of blood) significantly increased intracellular
& LDH leakage. This pertains to the hepatocytes of control rats as well as those of rats fasted for 24 and 48. hr. These effects might be come from the membrane-stabilizing effects of calcium. But calcium had no effects on cell volumes, superoxide-formation and glucose uptake. Actually hepatocytes of starved rats showed changes in several cellular parameters. Starvation increased LDH leakage, glucose uptake and the total concentration of
whereas it markedly decreased cell volumes. Since total tonicity remained unchanged, intracellular
could contribute to a higher share of total osmolarity in starvation. Starvation increased the cytoplasmic pH because
ions and their corresponding counterions disappeared. This increase may be related to suppress the protonization of amino groups in proteins. Starvation decreased hepatic glycogen, a major compound that affects cytosolic volume of hepatocytes. The data indicate that starvation increases the glucose transport activity. The possible molecular basis will be discussed.
A Study on the metabolism mechanism of Benzene, Toluene and Xylene by Cytochrome P-450 dependent radical-mediated
Toxicological Research, volume 11, issue 2, 1995, Pages 205~213
This study was undertaken to investigate the effects of organic solvents on xenobiotic metabollzing enzyme system in vivo by meaas of experimental conditions i.e. (1) single group which was treated by benzene (B), toluene (T) and xylene (X), respectively, (2) combination group which was treated by mixture of benzene+toluene (BT), benzene+xylene (BX), and toluene+xylene (TX), respectively, (3) mixture group which was treated by benzene+ toluene+xylene mixture (M), and to interpreat the interaction between the organic solvents metabolizing enzymes. 1. The contents of cytochrome P-450 in liver microsomes were increased (p < 0.01) in organic solvents treated groups, and the contents of cytochrome P-450 were increased by following order of B < T < M < BT=BX < X < TX. 2. The activity of cytochrome P-450 dependent AHHase was significantly higher in organic solvents treated groups than in control group (p < 0.01), and the activity of AHHase was increased by following order of B < T < BT=BX=TX=xylene < M. 3. The activity of NADPH P-450 reductase was significantly higher in organic solvents treated groups than in control group (p < 0.01), and the order of M < combinated group < X < T
Long-Term Feeding of Dietary Fat and Butylated Hydroxytoluene on The Hepatic Microsomal Mixed-Function Oxidase System in 2-Acetylaminofiuorene Treated Rats
Kim, Kyung-Min ; Yim, Kyeong-Sook ; Choi, Hay-Mie ;
Toxicological Research, volume 11, issue 2, 1995, Pages 215~221
This paper examines the effects of dietary polyunsaturated fatty acid/saturated fatty acid (p/s) ratios and butylated hydroxytoluene (BHT) on the hepatic microsomaI mixed-function oxidase sy. stem in 2~acetylaminofiuorene (2-AAF) treated rats. Sprague-Dawley male rats were fed the diet of beef tallow (p/s 0.08), beef tallow plus soybean oil (p/s 1.0), and soybean oil (p/s 4.0) at the level of 15%fat and with or without 0.3% BHT. After 2-AAF was injected twice at the ages of 23 and 27 weeks, cholesterol/phospholipid molar ratio, thiobarbituric acid reactive substances (TBARS) level, cytochrome P450, cytochrome
, and NADPH-cytochrome c reductase activity were measured from isolated hepatic microsomal fractions. In the beef tallow (p/s 0.08) and beef tallow plus soybean oil (p/s 1.0) groups, cholesterol/phospholipid molar ratio showed decreasing tendency by 2-AAF and BHT. Cytochrome P-450 content was decreased in the group of soybean oil (p/s 4.0) and NADPH-cytochrome c reductase activity was increased by 2-AAF and BHT in all the dietary groups. While TBARS levels were increased by 2-AAF in all the dietary groups, they were reduced by BHT in the soybean oil (p/s 4.0) group. These results suggest that long term intake of soybean oil (p/s 4.0) diet induced changes in the nature of microsomal membrane and induced less cytochrome P-450, low level feeding of BHT increased cytochrome c reductase activity and lowered microsomal lipid peroxidation levels, which were increased by 2-AAF treatment.
Development of Antitoxic Agents from Korean Medicinal Plants. Part 2. Effects of Lonicerae flos Extract on the Accumulation of Cadmium in Liver
Toxicological Research, volume 11, issue 2, 1995, Pages 223~227
This study was conducted to investigate the metallothionein (MT) induction by Lonicerae rios in cadmium chloride intoxication. The results were as follows: Generally, detoxication effects by Lonicerae fios extract increased to the increase of extract concentrations. When 90 mg/kg dosage of Lonicerae fios extract was administered, it showed the highest antitoxic effects in metallothionein induction. From the above results, Lonicerae rios extract increased metallothionein concentration and decreased the toxicity of cadmium in liver.
Development of Antitoxic Agents from Korean Medicinal Plants (Part 3) Repaired Effects of Methanol Fraction of Perilla Frutescens on 3T3 Fibroblast Treated with Cadmium
Toxicological Research, volume 11, issue 2, 1995, Pages 229~234
This study was carried out to evaluate the cytotoxicity of cadmium on 3T3 fibroblast and to develop the antidote on 3T3 fibroblast which was injuried by
of cadmium. The groups for repaired effects were divided into 7 groups such as medium alone treated group. Cadmium treated
groups and 5 experimental groups
concentration of each methanol fraction). After incubation for 48 hrs in the same conditions, MTT (tetrazolium MTT), NR (neutral red) and SRB (sulforhodamine B protein) assay were measured. Light microscopic observations were also investigated. The ethyl acetate fraction of Perilla frutescens showed significantly repaired effect against cadmium cytotoxiclty and this fraction inhibited critical cell regeneration in light microscopy.
Development of Antitoxic Agents from Korean Medicinal Plants. Part 4. Effects of Panax ginseng C. A. Meyer Extract on the Accumulation of Cadmium in Liver
Toxicological Research, volume 11, issue 2, 1995, Pages 235~239
This study was conducted to investigate the metallothionein (MT) induction by Panax ginseng C. A. Meyer in cadmium chloride intoxication. The results were as follows: Generally, detoxicatlon effects by Panax ginseng C. A. Meyer extract increased proportionally to the increase of cadmium concentrations. When a 8 mg/g dosage of cadmium was administered, formation of the cadmium and EDTA complex showed the highest antitoxic effect. Also, when a 4 mg/g dosage of cadmium was administered, Panax ginseng C. A. Meyer extract showed the highest antitoxic effect in metallothionein induction. According to the above results, Panax ginseng C. A. Meyer extract administered with cadmium increased metallothionein concentration and decreased the toxicity of cadmium in liver.
Development of Antitioxic Agents from Korean Medicinal Plants. Part 5. Antitoxic Effects of Binding of Caffeic acid and Cadmium on Cultured Rat Neuroglial Cells
Toxicological Research, volume 11, issue 2, 1995, Pages 241~246
This study was carried out to develop the antitoxic compound about cytotoxicity of cadmium on cultured rat neuroglial cells. These cells divided into 3 groups; control group (medium only) or
group (neuroglial cell,
cadmium) and experimental group (
caffeic acid). Neutral red (NR) and tetrazolium MTT of the colorimetric assay were performed to evaluate the cytotoxicity of cell organelles. The light microscopic study was carried out to morphological changes of cultured rat neuroglical cells. The results indicated that caffeic acid showed detoxification effect on cytotoxicity of cadmium in
concentration. According to the spectroscopic study of 1:1 complex of cadmium and caffeic acid, it showed that this formation of complex eliminated cadmium from cultured rat neurogllal cells.
Effect of Allopurinol Pretreatment on the Liver Damage in
Toxicological Research, volume 11, issue 2, 1995, Pages 247~252
To evaluate the effect of xanthine oxidase on liver injury by
, liver damage was induced both in allopurinol pretreated rats (500 mg/kg. ip) and control group by twice intraperitoneal injection of
(0.1 ml/100 g body wt. 50% in olive oil) at interval of one day. Increases in the levels of serum alanine aminotransferase and liver weight/body weight (%) by
were significantly smaller inallopurinol pretreated rats than in control whereas the hepatic microsomal glucose-6-pholphatase activities were significantly higher in allopurinol pretreated rats than control group by
treatment. These results indicates that allopurinol pretreatment may reduce the liver damage in
intoxicated rats. In rats either with
or not, hepatic type O xanthine oxidase activities were significantly reduced by allopurinol pretreatment and the increasing rate of these enzymes to each control was remarkably lower in allopurinol pretreated rats than control. Liver cytosolic protein contents and aniline hydroxylase, aminopyrine demethylase activities were higher in allopurinol pretreated rats than coirol rats when animals were treated with
. On the other hand, neither allopurinol pretreated nor
treatment caused any significant changes in hepatic superoxide dismutase and catalase activities. Hepatic glutathione contents were higher in
-treated rats than control, but no significant changes were found in both between the allopurinol treated rats and
-treated rats pretreated with allopurinol, and glutathione and glutathione S-transferase activities were significantly reduced in
-treated rats than control whereas these enzyme activities showed on significant change in both between allopurinel treated and
-treated rats pretreated with allopurinol. It is concluded that xanthine oxidase reaction system augment
induced liver injury via even oxygen free radical system.
Effect of Ethanol Pretreatment on the Bromobenzene Metabolism in Rats
Toxicological Research, volume 11, issue 2, 1995, Pages 253~259
To investigate an effect of ethanol pretreatment on the bromobenzene metabolism, the brornobenzene (400 mg/kg body wt. i. p.) was given 3 times at intervals of one day to the male rats orally pretreated with 5% ethanol throughout 2 months. In the ethanol pretreated rats, liver injuries were not demonstrated on the basis of the liver weight per body weight, serum levels of alanine aminotransferase (ALT) activity and histopathologic findings. By the bromobenzene treatment, ethanol pretreated rats showed the more decreased levels of serum ALT and liver weight/body weight(%), and decreased degree of liver damage on histopathological observation than the control group. The ethanol pretreated rats showed the more increased activities of hepatic aniline hydroxylase, glutathione Stransf erase (GST) and the more decreased contents of glutathione than the control. Concomitantly the ethanol pretreated rats showed the more decreased contents of hepatic glutathione and increased activities of GST by the bromobenzene treatment. Above results indicate that ethanol pretreatment enhance the metabolizing ability of bromobenzene in rats.
Age-related Increase of Sister Chromatid Exchange Frequency in Bone Marrow Cells of Senescence Accelerated Mouse and Its Inhibition by Chronic Treatment of Ginseng
Lim, Heung-Bin ; Sohn, Hyung-Ok ; Lee, Young-Gu ; Kim, Seung-Hyung ; Lee, Dong-Wook ;
Toxicological Research, volume 11, issue 2, 1995, Pages 261~266
Age-related change in the frequency of spontaneous sister chromatid exchange (SCE) and chromosornal aberrations were investigated in bone marrow cells of accelerated senescence-resistant mice (SAM R1) and senescence accelerated ones (SAM P1). And the effect of chronic treatment of ginseng extract (Panax ginseng C.A. Meyer) on these chromosomal abnormalities was tested in SAM P1. SCE frequency in the cells was progressively increased with age in both mice, but it was consistently higher in SAM P1 than in SAM R1 at all corresponding age. Chromosomal aberrations were, however, not significantly changed with age except that it was slightly increased in only aged SAM P1. Interestingly, the rate of these genetic instabilities in SAM P1 was remarkably retarded by long-term administration of ginseng water extract (0.05% in drinking water). These results suggest that frequency of spontaneous SCE in bone marrow cells increase in parallel with senescence of the mice, and SAM P1 is in the condition of being more exposed than SAM R1 to DNA damaging factors. These also indicate that long-term treatment of ginseng may reduce the genetic damage.
Decreased Induction of Alcoholic Fatty Liver by YH430 in Rats
Toxicological Research, volume 11, issue 2, 1995, Pages 267~271
A single large dose of ethanol as well as chronic ethanol consumption produces alcoholic fatty liver in human and experimental animals. We examined the effects of YH439, a potential hepatoprotective agent, on alcoholic fatty liver generation in adult female rats. In rats treated with YH439 (250 mg/kg, po) 4 hr prior to a single dose of ethanol (6 g/kg, po), a significant decrease in hepatic triglyceride accumulation was observed. YH439 also has an inhibitory effect on hepatic triglyceride and cholesterol accumulation induced by repeated ethanol treatments for one week. Because it has been known that induction of alcoholic fatty liver is associated with lipid peroxidation and/or hepatic glutathione depression, the effect of YH439 on these parameters was determined in the livers of rats treated with ethanol. Coadministration with YH439 inhibited MDA formation and gIutathione depression induced by acute or repeated ethanol administration. In order to determine the effect of YH439 on ethanol metabolism in vivo, disappearance of ethanol from blood was measured. In rats treated with a single dose of ethanol (6 g/kg, po), the ethanol concentration in blood reached a peak approximately 120 min following the treatment which declined linearly for 18 hrs. YH439 had no effect on the decline of blood ethanol concentration regardless of the dose of ethanol given to rats. These results in this study suggest that YH439 has an inhibitory effect on fatty liver generation induced by acute or repeated ethanol consumption through a mechanism not directly related to the rate of ethanol metabolism in vivo.
Alterations in Dichloromethane-Induced Carboxyhemoglobin Elevation by Several Metabolic Modulators
Toxicological Research, volume 11, issue 2, 1995, Pages 273~277
Several metabolic modulators on the generation of carbon monoxide (CO)from dichloromethane (DCM) was examined in adult female rats. It has been known that DCM is converted to CO by cytochrome P-450 or to carbon dioxide
by glutathione-dependent metabolic reaction. In rats treated with DCM (3 mmol/kg, ip) only, the carboxyhemoglobin (COHb) level reached a peak of approximately 10% 2 or 3 hr following the treatment. Disulfiram (300 mg/kg, ip) or allylsulfide (200 mg/kg, po), both known as a selective inhibitior for cytochrome P-450 2E1, blocked the increase in COHb concentratlons almost completely suggesting that the metabolic conversion of DCM to CO is mediated by the activity of this specific type of isozyme. YH439 (125 or 250 mg/kg, po), a potential hepatoprotective agent, decreased the COHb elevation as well indicating that this chemical is a potent inhibitor for 2E1. In rats treated with pyrazine (200 mg/kg, ip) 18 hr prior to DCM the peak COHb concentration was decreased by approximately 3 or 4%. However, pretreatment of rats with pyrazine either 24 or 48 hr before DCM increased the peak COHb concentration significantly compared to the rats treated with DCM only. The results in the present study strongly suggest that the generation of CO from DCM depends on the 2E1 activity and that the pharmacological and/or toxicological action of YH439 or pyrazine in animals or human is associated with its effect on this isozyme.
Effect of Toluene Administration on the Activity of Serum Xanthine Oxidase in Rats
Toxicological Research, volume 11, issue 2, 1995, Pages 279~288
To apply the serum xanthine oxidase (XO) determining for the index of the toluene intoxication, the serum XO activity was compared with the other parameters, the activities of serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), 5'-nucleotidase(5'-NT), alkaline phosphatase(ALP), guanase(GDA) and
-gIutamyl transpeptidase(T-GTP). Concomitantly, the cause of increased level of serum XO was clarified in the present experimental conditions. Although the other serum enzyme activities, ALT, AST, 5'-NT, ALP, GDA and
-GTP were respectively not found to be different between control group and toluene-treated group, the serum XO activity in toluene-treated group showed the higher levels than that in the control group. These suggested that the determination of serum XO activity could be used for monitoring the intoxication of toluene. On the other hand, the activities of XO both in the serum and liver were higher in toluene-treated or benzaldehyde-treated rats than those in each control group. In the pooled liver XO from each group, toluene-treated or benzaldehyde-treated group showed the higher
value than the control group, whereas no changes were observed in liver XO activities between the control liver specimen and that preincubated with bertzaldehyde in vitro. The present results indicate that the increased level of XO in toluene-treated rats is due to the result of enzyme protein induction in liver cell by the benzaldehyde metabolized from toluene. All the more, the benzaldehyde may be acted as a substrate for XO, since the benzaldehyde induced the increased activity of both liver and serum XO, and no changes were found in purine catabolite, uric acid in serum or urine and liver purine catabolizing enzymes, adenosine deaminase, GDA, uricuse except XO in toluene-treated rats.
Effect of Toluene Treatment on the Xanthine Oxidase and Superoxide Dismutase Activities in Leukocyte of Bacterial Infected Rats
Toxicological Research, volume 11, issue 2, 1995, Pages 289~294
This study was designed to observe the effect of tohiene pretreatment on leukocyte variation in whole blood and the oxygen free radical generating, scavenging enzyme activities in neutrophil of bacteria infected rats. Toluene was administered 7 times intraperitoneally at levels of 9.45 mM/kg body weight to the rats and then infected with S. aureus
cfu/ml. The toluene treated-rats showed the significantly decreased numbers of lymphocyte and monocytes, but the similiar numbers of neutrophils with the control. Furthermore the increased neutrophils in blood of bacteria infected rats were reduced by the toluene pretreatment. Concomitantly the increased activities of xanthine oxidase and superoxide dismutase in neutrophil of bacteria infected rats were also decreased by the toluene pretreatment. On the other hand, injection of benzaldehyde to rats also led to similiar results in the count of leukocytes, xanthine oxidase and superoxide dismutase activities of neutrophil with those of toluene treated rats. These data suggest that toluene and its intermediate metabolite, benzaldehyde influence on the phagocytosis and defence mechanism of neutrophil.
Evaluation of Cytotoxicity to Rat Platelets by Menadione-Glutathione Conjugate and its Stability in Biological Assay System
Toxicological Research, volume 11, issue 2, 1995, Pages 295~302
Menadione-ghitathione conjugate (MEN-SG), a metabolite of menadione, is known to be a redoxcycler in rat hepatocyte subcellular fraction. Therefore, it was assumed that MEN-SG could exert cytotoxlclty to ral platelets, another target tissue of menadione. We first synthesized MEN-SG, the identity of which was verified by mass,
-NMR and UV-visible spectra. In addition, the stability of MEN-SG was investigated in biological assay system. MEN-SG was degraded in a time-dependent manner in DMSO which had been used as a vehicle and thus, tris-HCl buffer was used as a vehicle of MEN-SG despite the low solubility in it. Perchloric acid as well as platelets itself did not affect the stability of MEN-SG. Our next attempt was the evaluation of cytotoxicity of MEN-SG in rat platelets. MEN-SG did not induce cytotoxicity to rat platelets measured by two different methods, LDH release and turbidity changes. The extents of oxygen consumption by MEN-SG in intact platelets were significantly lower than those by menadione, though it had been observed that oxygen consumptions by menadione and MENSG were similar in subcellular fractioas of platelets. These results suggest that MEN-SG is not toxic to rat platelets despite its redox cycling capacity and glutathione conjugation reaction of menadione could be regarded as a detoxification process.
The Role of Nitric Oxide in Menadione-Induced Cytotoxicity in Rat Platelets
Toxicological Research, volume 11, issue 2, 1995, Pages 303~308
Nitric oxide, a physiological transmitter, is reported to mediate cellular injury in various tissues. Its reactivity to free radical is believed to be one of the reasons for its involvement in cytotoxicity. Menadione, a representative quinone, is cytotoxic to several cell systems including isolated hepatocyte, endothelial cell and red blood cells. Its toxic mechanism is related to oxidative stress, mediated by toxic free radicals. Our previous studies demonstrated that menadione induced cell lysis and increase of oxygen consumption in platelets. It has been reported that platelets have nitric oxide producing enzyme, nitric oxide synthase. Thus, we have investigated to manifest the role of nitric oxide.in menadione-induced cytotoxicity in rat platelets. Menadione induced cytotoxicity in platelets was unaffected by
-nitro-arginine methyl ester (L-NAME), selective and competitive inhibitor of nitric oxide synthase. We also invesitgated the role of extracellular nitric oxide in menadione-induced cytotoxicity of platelets by addition with sodium nitroprusside (SNP). SNP did not affect platelet cytotoxicity by menadione. These results suggested that nitric oxide which was generated endogeneously or exogeneously might have a negligible role in menadione-induced cytotoxicity in rat platelets.
The Liver Protective Activities of Some Iranian Medicinal Plants Against Liver Damage in Mice Induced by
Kalantari. H. ; Aghel. N. ; Annafecheh. M. ; Mar, Woong-Chon ; Chang, Il-Moo ;
Toxicological Research, volume 11, issue 2, 1995, Pages 309~313
The aim and objective of this study are to carry out the liver protective activities against the
intoxication in mice with some Iranian medicinal plants traditionally used for liver injuries. The methanol extracts of Cichorium intybus, Lactuca scarJoia, Eucalyptus camadulensis were evaluated. With various doses of these plants, liver protective activities were performed after
administration to mice. The serum aminotransferases activites, liver sizes, and histopatological examinations of liver were studied. At a dose of 50 mg/ kg, all three plants were able to protect liver damages induced by
The Neurotoxicological Alterations Induced by Narcotic Drugs and Industrial Chemicals in the Rat are Associated with Quantitative Changes in Glial Fibrillary Acidic Protein
Toxicological Research, volume 11, issue 2, 1995, Pages 315~327
Diverse neurotoxic insults result in proliferation and hypertrophy of astrocytes, a subtype of glia in central nervous system. The hallmark of this response, often terms "reactive gliosis", is the enhanced expression of the major intermediate filament protein of castrocytes, glial fibrillary acidic protein (GFAP). These changes in the astrocytes suggest that GFAP may be a useful biochemical indicator of neurotoxicity. To investigate this possibility, we administered intra-peritoneally prototype nerotoxicants, metharnphetamine (MAP, 5 mg/kg), cocaine (30 mg/kg), N-buthyl benzenesulfonamide (NBBS, 300 mg/kg) and trimethytin (TMT, 8 mg/kg) to Wistar Rats and then assessed the effects of these agents on content of GFAP, which were determined by Sandwish ELISA and evaluated with neurotoxic symptoms, and quantitative changes of imrnunoreactivity of GFAP by light microscopic image analysis in specific regions. We found that assay of GFAP revealed time- and region-dependant patterns of neurotoxicity. The GFAP immunoreactivity of rat brain was increased in substantia nigra and hippocampus by MAP, NBBS and TMT; in roedial septal nucleus and nucleus accurnbens, it was also increased by RrBBS. Sandwich ELISA showed that GFAP levels of cerebrum in all groups on days 3 and 7 and that of brainstem(including cerebellum) in MAP, NBBS groups on day 1 and 3 were increased. A review of the background, design and results of these experiments are presented in this paper. Our findings indicate that GFAP is a sensitive and specific biomarker of neurotoxicity.otoxicity.
Reaction Mechanism of Troleandomycin on the Activity of Human Liver Microsomal Cytochrome P450 3A4
Toxicological Research, volume 11, issue 2, 1995, Pages 329~335
Incubation of aflatoxin
with microsomes isolated from human liver number 110 yielded two metabolite peaks which were aflatoxin
-exo-8, 9-epoxide (exo-epoxide) in high performance liquid chromatography. Production ratio of $AFQ_1$ to exo-epoxide was 2.43$\pm $0.04. Metabolism of
and exo-epoxide was inhibited by troleandomycin in a same degree although troleandomycin was not activated as a mechanism-based inhibitor. The inhibitory effect was dependent upon either the incubation time with
or the preincubation time before the addition of
. Incubation of troleandomycin and NADPH by the microsomes resulted in the formation of a cytochrome P 450 (P450)-metabollc intermediate (MI) complex and the level was approximately 80% of total P450 3A4 in the microsomes. This figure was similar to that of the inhibitory effect of troleandomycin on $AFB_1$ metabolism. Glutathione which was reported that it prevented the formation of MI complex in rat liver microsomes did not inhibit the formation of MI complex in human liver microsomes. These results suggested that the inhibitory effect of troleandomycin on $AFB_1$ metabolism is due to the formation of MI complex with P450 3A4. And the reaction mechanism of troleandomycin by human liver microsomes might be dlfferent from that one by rat liver microsomes.