Thiram-induced toxic liver injury in male Sprague-Dawley rats

A single i.p. dose (120 mg/kg) of thiram given to male Sprague-Dawley rats caused a significant increase in the activity of SGOT and SGPT 24 hr post-treatment indicating liver damage. A considerable diminution in the serum cholinesterase activity was also noted in the treated rats as against the control animals. Additional evidence for thiram-induced liver toxicity is provided by the observation that there was approximately 50% inhibition of the activity of hepatic microsomal benzphetamine N-demethylase with a concomitant decrease in the concentration of cytochrome P-450, an important component of the mixed-function oxidase system. Although not significant, hepatic glutathione levels were also depleted by thiram, probably making the liver susceptible to toxic injury.     

Thiram‐induced toxic liver injury in male sprague‐dawley rats

Abstract

A single i.p. dose (120 mg/kg) of thiram given to male Sprague‐Dawley rats caused a significant increase in the activity of SGOT and SGPT 24 hr post‐treatment indicating liver damage. A considerable diminution in the serum cholinesterase activity was also noted in the treated rats as against the control animals. Additional evidence for thiram‐induced liver toxicity is provided by the observation that there was approximately 50% inhibition of the activity of hepatic microsomal benzphetamine N‐demethylase with a concomitant decrease in the concentration of cytochrome P‐450, an important component of the mixed‐function oxidase system. Although not significant, hepatic glutathione levels were also depleted by thiram, probably making the liver susceptible to toxic injury.     

Protective effects of seaweeds against liver injury caused by carbon tetrachloride in rats

Three species of seaweeds collected from Tung Ping Chau, Hong Kong, were screened for their hepatoprotective activity using carbon tetrachloride (CCl4)-induced liver injury in the rat as a model of chemical hepatitis. A single oral dose of 1.25 ml/kg of CCl4 was able to produce significantly elevated levels of serum glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transminase (GOT). Administration of 150, 300 and 600 mg/kg of aqueous extracts from Myagropsis myagroides, Sargassum henslowianum and S. siliquastrum, respectively, significantly reduced the CCl4-induced acute elevation in the levels of GPT and GOT in rats. The same result was also seen in the histopathological study of liver tissue. The seaweed crude extracts probably acted to protect against CCl4-induced liver injury through their antioxidant properties.     

Protective effects of isoflavone on some biochemical parameters affected by cypermethrin in male rabbits

Effect of isoflavone on cypermethrin-induced changes in enzyme activities and free radicals was studied in plasma, liver, brain and testes of male New Zealand White rabbits. Rabbits were orally given sublethal dose of cypermethrin (24 mg/kg BW; 1/100 LD50), while isoflavone (2 mg/kg BW) was given alone or in combination with cypermethrin. The tested doses were given to rabbits every other day for 12 weeks. Results obtained showed that cypermethrin significantly (P < 0.05) induced free radicals in plasma, liver, brain and testes. The activities of glutathione S-transferase (GST) (liver, brain and testes), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (liver and testes), and alkaline phosphatase (AlP) (liver) were significantly (P < 0.05) decreased due to cypermethrin administration. Contrariwise, the activities of GST, AST, ALT and AIP were increased in plasma. The activity of acetylcholinesterase (AChE) did not change in plasma and brain of treated rabbits with cypermethrin. Isoflavone alone significantly (p < 0.05) decreased the levels of free radicals in plasma, liver, brain and testes, while did not produce any significant effect on the investigated enzymes. However, isoflavone is able to reverse the changes in enzyme activities due to the effect of cypermethrin. Results concluded that isoflavone confers marked protection against cypermethrin-induced oxidative stress in rabbit's plasma, liver, brain and testes.     

Toxicological assessment of chlorinated diphenyl ethers in the rat

Chlorinated diphenyl ethers are environmental contaminants that have been found in Great Lakes fish and birds. Because of their presence in the food chain, and potential for human exposure, the present short-term study was conducted to assess their toxicity. Groups of 10 male and 10 female rats were each given by gavage 2,2',4,4'6-pentachlorodiphenyl ether (CDE1), 2,2',4,4',5,6-hexachlorodiphenyl ether (CDE2) or 2,2',3,3',4,6'-hexachlorodiphenyl ether (CDE3) at dose levels of 0.04, 0.4, 4.0 or 40 mg/kg b.w./day for a period of 28 days. The control group received an equivalent volume of corn oil only (0.5 ml/100 g b.w.). Treatment with the three CDE congeners did not result in suppression of growth rate or food consumption. Increased liver weights were seen in the animals of both sexes fed 40 mg/kg CDE2, in males treated with 40 mg/kg CDE1, and in females with 40 mg/kg CDE3. Hepatic microsomal aminopyrine demethylase activity was significantly higher in the male rats administered 40 mg/kg CDE2, and aniline hydroxylase activity was elevated in the females following the same treatment. Serum glucose, calcium, protein and urea nitrogen of CDE1-treated males were higher than the control. Levels of uric acid, potassium and LDH of CDE3-treated females were also elevated. No hematological changes were observed. Histological examination revealed that the liver and thyroid were the target organs affected by CDE treatment but the morphological changes were mild even at the highest dose level. Changes in the liver consisted of nuclear vesiculation and increased cytoplasmic volume. Alterations in the thyroid were characterized by increased epithelial height and follicular collapse. Based on the data presented above, the 3 CDE congeners can only be considered moderately toxic in the rat.     

Hepatotoxicity of monobromobenzene and hexabromobenzene: effects of repeated dosage in rats

The aim of the study was to determine whether monobromobenzene (BB) and hexabromobenzene (HBB) administered repeatedly (for 28 days) to female rats resulted in disturbances of heme synthesis. 5-Aminolevulinate dehydratase (ALA-D) and 5-aminolevulinate synthase (ALA-S) activities were slightly changed and the concentration of glutathione increased. The excretion of 5-aminolevulinic acid (ALA-U) in urine after all doses of BB and HBB increased already in the first week. After BB administration, increased excretion of coproporphyrins was detected only at the highest dose. The increased excretion of coproporphyrins following the administration of HBB could be observed already at the lowest dose (15 mg/kg). The excretion of uroporphyrins increased after two higher doses (75 and 375 mg/kg) in the fourth week of exposure. HBB also caused elevation of microsomal P450 level. The data suggest porphyrogenic activity of HBB; whereas in the case of BB we cannot exclude that elevated excretion of ALA-U resulted from kidney impairment.     

Toxicological assessment of chlorinated diphenyl ethers in the rat

Abstract

Chlorinated diphenyl ethers are environmental contaminants that have been found in Great Lakes fish and birds. Because of their presence in the food chain, and potential for human exposure, the present short‐term study was conducted to assess their toxicity. Groups of 10 male and 10 female rats were each given by gavage 2,2’,4,4'6‐pentachlorodiphenyl ether (CDE1), 2,2’,4,4’,5,6‐hexachlorodiphenyl ether (CDE2) or 2,2’,3,3’,4,6'‐hexachlorodiphenyl ether (CDE3) at dose levels of 0.04, 0.4, 4.0 or 40 mg/kg b.w./day for a period of 28 days. The control group received an equivalent volume of corn oil only (0.5 ml/100 g b.w.). Treatment with the three CDE congeners did not result in suppression of growth rate or food consumption. Increased liver weights were seen in the animals of both sexes fed 40 mg/kg CDE2, in males treated with 40 mg/kg CDE1, and in females with 40 mg/kg CDE3. Hepatic microsomal aminopyrine demethylase activity was significantly higher in the male rats administered 40 mg/kg CDE2, and aniline hydroxylase activity was elevated in the females following the same treatment. Serum glucose, calcium, protein and urea nitrogen of CDE1‐treated males were higher than the control. Levels of uric acid, potassium and LDH of CDE3‐treated females were also elevated. No hematological changes were observed. Histological examination revealed that the liver and thyroid were the target organs affected by CDE treatment but the morphological changes were mild even at the highest dose level. Changes in the liver consisted of nuclear vesiculation and increased cytoplasmic volume. Alterations in the thyroid were characterized by increased epithelial height and follicular collapse. Based on the data presented above, the 3 CDE congeners can only be considered moderately toxic in the rat.     

Effect of chronic exposure to cadmium on hepatic drug metabolism

In an attempt to examine the chronic effect of low levels of cadmium on hepatic drug-metabolizing enzyme system, an experiment was carried out in which growing male rats were given 0, 5, 10, and 20 ppm of cadmium in drinking water for a period of 8 weeks. An ip administration of a hypnotic dose of pentobarbital to the cadmium-treated and the control rats 24 hr following the termination of the experiment exhibited that there was no significant difference in the drug metabolism in control and any of the treated groups. Next, liver microsomes were isolated from animals in all groups to study their ability to metabolize drugs in vitro. The results indicated that the activity of benzphetamine N-demethylase and aniline hydroxylase, and the concentration of microsomal cytochrome P-450 were almost identical in the control and treated groups. On the other hand, a single ip dose of cadmium (2 mg/kg) caused significant decrease in the vivo and in vitro microsomal drug metabolism. These results suggest that although a single ip dose of cadmium (2 mg/kg) causes significant inhibition of drug metabolism, chronic exposure to cadmium up to 20 ppm in drinking water over a period of 8 weeks is unlikely to affect hepatic drug metabolism.     

Fungicidal impact on chickpea--Mesorhizobium symbiosis

The effects of carbendazim, captan, thiram, and mancozeb, on plant vitality, chlorophyll content, N uptake, protein content, nodulation, and seed yield in chickpea (Cicer arietinun) were assessed in a controlled environment. Seeds treated with fungicides at 1 and 1.5 g.a.i. kg seed had no significant adverse effect on plant vigor, seed yield, and N and protein contents. In contrast, fungicides applied at 2 g.a.i./kg of captan, thiram and mancozeb, significantly reduced the measured parameters. In general, the toxicity of fungicides in terms of seed yield increased in the following order: Control=carbendazim > thiram > captan > mancozeb. Total chlorophyll content in foliage declined consistently with fungicides dose rates and application days. Seeds treated with lower rates of fungicides significantly increased nodulation (nodule number per plant and its dry mass) and were compatible with chickpea inoculum used in this study. Although carbendazim at 2 g.a.i. kg seed had no phytotoxic effect assessed under greenhouse conditions, it significantly reduced the chlorophyll content, nodulation (60d) and N content in shoots.     

In-vivo interaction of some organophosphorus insecticides with different biochemical targets in white rats

A comparative study between five organophosphorus insecticides: Leptophos, EPN, Cyanofenphos, Chlorpyrifos and Diazinon, was carried out for acute oral toxicity to white rats and for their in vivo interaction at 1/10th of LD50 doses with the activity of six serum enzymes after 4 wks from oral administration. Leptophos, Chlorpyrifos and diazinon exerted significant inhibition particularly to glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), glutamyltransferase (GT) and lactate dehydrogenase (LDH). Adding ascorbic acid in the diet at 0.5% enhanced the acute oral toxicity of leptophos, chlorpyrifos and diazinon. For all the compounds, presence of ascorbic acid protected a number of the monitored serum enzymes from being inhibited except for leptophos. Ascorbic acid caused hypoglycemia with sublethal doses of leptophos, chlorpyrifos, and diazinon. The synergist piperonyl butoxide alone at 750 mg/kg dose inhibited the activity of the six serum enzymes. Presence of ascorbic acid in the diet intensified the inhibitory effect of piperonyl butoxide to all enzymes except for GOT.     

Effect of chronic exposure to cadmium on hepatic drug metabolism

Abstract

In an attempt to examine the chronic effect of low levels of cadmium on hepatic drug‐metabolizing enzyme system, an experiment was carried out in which growing male rats were given 0, 5, 10, and 2 0 ppm of cadmium in drinking water for a period of 8 weeks. An ip administration of a hypnotic dose of pentobarbital to the cadmium‐treated and the control rats 2 4 hr following the termination of the experiment exhibited that there was no significant difference in the drug metabolism in control and any of the treated groups. Next, liver microsomes were isolated from animals in all groups to study their ability to metabolize drugs in vitro. The results indicated that the activity of benzphetamine N‐demethylase and aniline hydroxylase, and the concentration of microsomal cytochrome P‐450 were almost identical in the control and treated groups. On the other hand, a single ip dose of cadmium (2 mg/kg) caused significant decrease in the in vivo and in vitro microsomal drug metabolism. These results suggest that although a single ip dose of cadmium (2 mg/kg) causes significant inhibition of drug metabolism, chronic exposure to cadmium up to 2 0 ppm in drinking water over a period of 8 weeks is unlikely to affect hepatic drug metabolism.     

Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice.

The effect of mercuric chloride (HgCl2) on the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and its effect on glutathione (GSH) content were evaluated in different organs (liver, kidneys, and brain) of mice after administration at 0, 0.25, 0.5 and 1.0 mg/kg/day for 14 days. The uptake of mercury shows that the kidneys accumulated the highest levels of mercury compare to brain and liver. The enzyme levels varied in mercury treated organs compare to control. A dose dependent increase of antioxidant enzymes occurred in the liver and kidneys. The increase in enzyme activities correlated with highest mercury accumulation in the kidneys and liver. Mercury is known to generate reactive oxygen species (ROS) in vivo and in vitro, therefore, it is likely that enzyme activities increased to scavenge ROS levels produced as a result of mercury accumulation. Glutathione content increased in liver and kidneys of mercury treated mice compare to control. The results showed that the highest oral dose of mercury significantly increased antioxidant enzymes in kidneys and liver. The increased antioxidant enzymes enhance the antioxidant potential of the organs to reduce oxidative stress.     

Effect of some xenobiotics on kynurenine hydrolase and kynurenine aminotransferase of mouse liver

The effects of some xenobiotics on the activity of the B6-dependent kynurenine hydrolase (KH) and kynurenine aminotransferase (KATE) in mouse liver, were investigated. Polychlorinated biphenyl (Aroclor 1254) (400mg/kg/day x4) markedly decreased the activity of both enzymes. Benzo(a)pyrene (BP) and 3-methylcholanthrene (3-MC) (40mg/Kg/day x1) as well as phenobarbital (PB) (75mg/kg/day x3) did not alter the activity of KH, while that of KATE was mildy reduced. The response of the two enzymes to treatment with chlorpromazine (CPZ) (5mg/Kg/day x5) were opposite with marked elevation of KH and inhibition of KATE activities. Treatment with B-naphthoflavone (B-NF) (80mg/Kg/day x2), Pyrazole (200mg/Kg/day x1) or indole (400mg/kg/day x1) produce no change in the activity of either enzyme. It, seems therefore, that Aroclor (1254) and chlorpromazine may cause disordered kynurenine metabolism through alterations in the activities of its metabolizing enzymes. This, in turn, might affect nicotinamide adenine dinucleotide biosynthesis and/or the accumulation of some tryptophan metabolites suspected of being carcinogenic or co-carcinogenic.     

Accumulation of mercury and its effect on antioxidant enzymes in brain,liver, and kidneys of mice

Abstract

The effect of mercuric chloride (HgCl₂) on the activities of catalase, Superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and its effect on glutathione (GSH) content were evaluated in different organs (liver, kidneys, and brain) of mice after administration at 0, 0.25, 0.5 and 1.0 mg/kg/day for 14 days. The uptake of mercury shows that the kidneys accumulated the highest levels of mercury compare to brain and liver. The enzyme levels varied in mercury treated organs compare to control. A dose dependent increase of antioxidant enzymes occurred in the liver and kidneys. The increase in enzyme activities correlated with highest mercury accumulation in the kidneys and liver. Mercury is known to generate reactive oxygen species (ROS) in vivo and in vitro, therefore, it is likely that enzyme activities increased to scavenge ROS levels produced as a result of mercury accumulation. Glutathione content increased in liver and kidneys of mercury treated mice compare to control. The results showed that the highest oral dose of mercury significantly increased antioxidant enzymes in kidneys and liver. The increased antioxidant enzymes enhance the antioxidant potential of the organs to reduce oxidative stress.     

Effect of some xenobiotics on kynurenine hydrolase and kynurenine aminotransferase of mouse liver

Abstract

The effects of some xenobiotics on the activity of the B₆‐dependent kynurenine hydrolase (KH) and kynurenine aminotransferase (KATE) in mouse liver, were investigated. Polychlorinated biphenyl (Aroclor 1254) (400mg/kg/day ×4) markedly decreased the activity of both enzymes. Benzo(a)pyrene (BP) and 3‐methylcholanthrene (3‐MC) (40mg/Kg/day ×1) as well as phénobarbital (PB) (75mg/kg/day ×3) did not alter the activity of KH, while that of KATE was mildy reduced. The response of the two enzymes to treatment with chlorpromazine (CPZ) (5mg/Kg/day ×5) were opposite with marked elevation of KH and inhibition of KATE activities. Treatment with B‐naphthoflavone (B‐NF) (80mg/Kg/day ×2), Pyrazole (200mg/Kg/day ×1) or indole (400mg/kg/day ×1) produce no change in the activity of either enzyme. It, seems therefore, that Aroclor(1254) and chlorpromazine may cause disordered kynurenine metabolism through alterations in the activities of its metabolizing enzymes. This, in turn, might affect nicotinamide adenine dinucleotide biosynthesis and/or the accumulation of some tryptophan metabolites suspected of being carcinogenic or co‐carcinogenic.     

Role of alpha-tocopherol and beta-carotene in ameliorating the fenvalerate-induced changes in oxidative stress, hemato-biochemical parameters, and semen quality of male rats

Role of alpha-tocopherol (vitamin E), beta-carotene and/or their combination as antioxidants against the toxicity of fenvalerate on blood hematology, free radicals, biochemical parameters, and semen quality were studied in male rats. Fenvalerate (20 mg/kg BW), vitamin E (100 mg/kg BW), beta-carotene (10 mg/kg BW), and vitamin E plus beta-carotene (100 + 10 mg/kg BW, respectively) were given alone or in combination with fenvalerate. The tested doses were given to rats every other day for 30 days. Results obtained showed that fenvalerate significantly (P < 0.05) induced free radicals in plasma and brain and insignificantly in liver and testes. While, vitamin E, beta-carotene alone and/or in combination decreased the levels of free radicals in plasma, liver, testes, and brain. The activities of glutathione S-transferase (liver), alkaline phosphatase (plasma and liver), aspartate aminotransferase (plasma, liver, and testes) and alanine aminotransferase (plasma and liver) were significantly (P < 0.05) increased due to fenvalerate administration. The activity of acetylcholinesterase was significantly (P < 0.05) decreased in brain and plasma, while plasma glucose, urea, creatinine, and bilirubin concentrations were significantly (P < 0.05) increased in rats treated with fenvalerate. Also, results showed a significant (P < 0.05) alterations in plasma proteins, hematological parameters, body weight, and relative weights of organs. Sperm concentration and motility (%) were significantly (P < 0.05) decreased, while dead and abnormal sperm increased in rats exposed to fenvalerate. Vitamin E, beta-carotene alone and/or in combination did not cause any changes in the investigated parameters, but improved semen quality and minimized the toxic effect of fenvalerate. The obtained results demonstrated the beneficial influences of vitamin E, beta-carotene alone and/or in combination in reducing the harmful effects of fenvalerate.     

Excretion and toxicity of Cyolane in the rat

The excretion of ¹⁴C-labelled Cyolane, 24 hours after single oral application was found to be about 50% of the applied dose in urine, faeces and expired air.The activity of Acetylcholine esterase in brain, plasma and erythrocytes, and liver succinate dehydrogenase was studied for 16 weeks in 4 groups of rats after repeated orally daily doses of Cyolane, 0.9, 0.45, 0.09 and 0.045 mg/kg.It has been found that at all the dose levels there were cumulative inhibition effects in brain and blood choline esterase and liver succinate dehydrogenase till the 2nd week and then there was a recovery at low dose rates in blood choline esterase and liver succinate dehydrogenase activities. After 6 - 16 weeks the effects were nearly compensated. At higher doses almost all the rats died after 6 weeks due to the insecticide toxicity.     

Toxicological properties of trialkyl phosphorothioate and dialkyl alkyl- and arylphosphonothioate esters

Impurities such as O,S,S-trimethyl phosphorodithioate (TMPD) and the S-methyl isomer of malathion (isomalathion) strongly potentiated the mammalian toxicity of malathion. In contrast, impurities present in the phosphoramidothioate insecticide acephate had an antagonizing effect on its mammalian toxicity. The potentiation of the toxicity of malathion was attributed to inhibition of mammalian liver and serum carboxylesterase. O,O,S-Trimethyl phosphorothioate (TMP), another impurity present in technical malathion and in other organophosphorus insecticides, proved to be highly toxic. Rats given a single oral dose of TMP at a level as low as 20 mg/kg died over a period of three weeks, with death occurring with non-cholinergic signs of poisoning. TMPD also caused similar delayed death in rats. O,O,O-Trimethyl phosphorothioate (TMP=S), also another impurity in technical malathion and a structural isomer of TMP, was a potent antagonist to the delayed toxicity of TMP. Examination of a number of related trialkyl phosphorothioate and dialkyl alkylphosphonothioate esters revealed several of these compounds to be highly toxic to rats.     

Fate of ochratoxin A in goats.

The fate of ochratoxin A (OA) was studied in goats given a single oral dose of 3H-OA (0.5 mg/kg). More than 90% of the radioactivity was found to be excreted in 7 days and the majority (53%) was found in feces. Thirty-eight percent, 6% and 2.26% of the activity was found in urine, milk and serum, respectively. The radioactivity in the liver and kidney 6 hours after feeding amounted to 1.5 and 0.5% of the total dose administered, respectively. Subsequent fractionation of liver and kidney homogenates revealed that microsomes, ribosomes and post-ribosomal supernatant fractions contained most radioactivity. Thin layer chromatographic analyses revealed two additional radioactive spots with Rf values and fluorescent characteristics different from OA, Oalpha and 4-OH-OA. Whereas OA was found as the unaltered molecule in feces, the metabolites were primarily found in urine and milk. Less than 0.03% of free OA was found in milk during the 7-day period.     

Protective effects of sodium bicarbonate on murine ochratoxicosis

The protective effect of sodium bicarbonate (NaHCO3), a urine modifier, to alleviate murine ochratoxicosis was investigated. The study included two trials. Urinary pH was altered before oral administration of ochratoxin A (OA) in Trial 1, and animals were given combined doses of OA and ethyl biscoumacetate (Eb) in Trial 2. Acute toxicity of OA as measured by LD50 values was reduced by 23% and 20% in rats treated with NaHCO3 for Trials 1 and 2 respectively. Bicarbonate-treated rats dosed with 20 mg/kg OA or with a combination dose of OA at 17 mg/kg and Eb at 50 mg/kg, had a lower frequency of histological lesions in kidneys, liver, lung, spleen and heart. Two types of heart lesions found in the present study are described.