Kinetic studies on the inhibition of creatine kinase activity by 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one in the cerebral cortex of rats.

Tellurium has been used as an industrial component of many alloys and in the electronic industry. Organotellurium compounds can cause poisoning which leads to neurotoxic symptoms such as significant impairment of learning, spatial memory and are potentially neurotoxic to human beings. However, the molecular mechanisms of neurotoxicity of organotellurium compounds are not well understood. Considering that creatine kinase plays a key role in energy metabolism of tissues with intermittently high and fluctuating energy requirements, such as nervous tissue, the main objective of this study was to investigate the mechanisms by which 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one inhibit creatine kinase activity, a key enzyme of energy homeostasis, in the cerebral cortex of 30-day-old Wistar rats. For the kinetic studies, the Lineweaver-Burk plot was used to characterize the mechanisms of enzyme inhibition by 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one. The results suggested that this compound inhibits creatine kinase activity by two different mechanisms: competition with ADP and oxidation of critical sulfhydryl groups for the functioning of the enzyme. The potential for inhibition of creatine kinase to occur in vivo may contribute to the neurotoxicity observed by this organochaocogen.

Toxicological evaluation of chronic exposure to the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one in male rats.

The aim of this study was to evaluate the effect of chronic treatment with the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some behavioral and biochemical parameters in the brain, liver, kidney and serum of 90-day-old male Wistar rats. The animals received the organoselenium at doses of 125, 250 or 500 µg/kg body weight intraperitoneally once daily for 30 days. Results showed that chronic treatment with this compound induced behavioral changes in animals, such as increasing of rearing at dose of 250 µg/kg and increasing of ambulation in all concentrations tested. On the other hand, we did not observe any alterations in the body weight gain of the animals. Moreover, the activity of the enzyme creatine kinase (CK) decreased in the cerebral cortex, cerebellum and kidney and increased in the liver after the chronic treatment with the organoselenium compound at dose of 500 µg/kg. The compound also increased aspartate aminotransferase (AST) and urea levels in serum of rats at 500 µg/kg. Glucose, cholesterol, triglycerides, creatinine, alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels were not changed by the treatment. Our results thus show that chronic administration of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one is able to significantly change the activity of CK in Wistar rats, resulting in a change in cellular energy homeostasis in these tissues, liver damage and behavioral changes in the animals studied.

Acute administration of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces biochemical and hematological disorders in male rats.

Organochalcogens are extensively produced and employed by industry and agriculture, and the risk of occupational and environmental toxicity to them has been poorly understood. Here, we investigated the acute effect of a new organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on biochemical and hematological parameters in male Wistar rats. The animals were treated with a single intraperitoneal injection of the organochalcogen at doses of 125, 250 or 500 µg·kg(-1). After 60 min, the animals were sacrificed by decapitation, and the trunk blood was collected for determination of glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, urea, creatinine, C-reactive protein, red blood cells, hematocrit, hemoglobin and white blood cells (WBC). Our results showed a reduction in cholesterol levels in all treated groups, an increase in ALT activity at doses of 250 and 500 µg·kg(-1), a decrease of hemoglobin and an increase in WBC in animals that received 250 and 500 µg·kg(-1) of the organoselenium. In addition, we observed an increase in neutrophil counts at 125 µg·kg(-1) dose and a decrease at 500 µg·kg(-1) dose. We also verified an increase in lymphocyte counts at the dose of 500 µg·kg(-1). Thus, the present study shows that the acute treatment with this new organochalcogen causes biochemical changes and hematological disorders in male rats.

Acute treatment with the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one produces behavioral changes and inhibition of creatine kinase activity in the brain of rats.

Organotellurium compounds have been synthesized since 1840, but their pharmacological and toxicological properties are still incipient. Therefore, the objective of this study was to verify the effect of acute administration with the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on the activity of brain creatine kinase (CK), a key enzyme in energy metabolism, and on behaviors in the open field test of 30-day-old rats. Animals were treated intraperitoneally with a single dose of the organotellurium (125, 250, or 500 µg/kg body weight) and after 55 min of the drug administration the open field test was carried out. Behavior analyses were performed during 5 min and the number of the squares crossed, number of rearing, number of groomings and number of fecal boli were recorded by an observer. Then, the animals were sacrificed and the cerebral cortex, the hippocampus, and the cerebellum were dissected, and CK activity and sulfhydryl content were measured in the brain. The organotellurium increased the ambulation and rearing behaviors in the open field test at doses of 250 and 500 µg/kg. Moreover, the compound inhibited CK activity and provoked a reduced of thiol content measured by the sulfhydryl assay in all the tissues studied. Therefore, changes in energy homeostasis and motor behavior in rats treated with this organotellurium support the hypotheses that the brain is a potential target to pharmacological and toxicological effects of this compound.

The organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces oxidative stress in heart, liver, and kidney of rats.

The objective of this study was to investigate the in vitro effects of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress in liver, kidney, and heart of 10-day-old rats. The homogenates of liver, kidney, and heart were incubated for 1 h in the absence (control) or in the presence of 1, 10, or 30 µM of the organoselenium and thiobarbituric acid reactive substances, carbonyl, and the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were measured. First, we tested the influence of the compound on 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)) radical scavenging and verified that the organochalcogen did not have any antioxidant properties. We observed an increase of lipid peroxidation in all concentrations tested in heart and kidney, while in liver only in the concentrations of 10 and 30 µM. Moreover, we also verified an enhance of protein oxidation in the concentrations of 10 and 30 µM in kidney. On the other hand, the compound caused a reduction on the activity of CAT in heart (10 and 30 µM), liver (30 µM), and kidney (30 µM). The activity of SOD was increased in heart (10 and 30 µM), while in liver (30 µM) and in kidney (10 and 30 µM) the activity was reduced. Our findings indicate that this organoselenium compound induces oxidative stress in liver, heart, and kidney of immature rats, collaborating to the fact that these tissues are potential targets for the organochalcogen action.

An in vitro comparison of a new vinyl chalcogenide and sodium selenate on adenosine deaminase activity of human leukocytes.

Selenium (Se) is a dietary essential trace element with important biological roles. Sodium selenate (Na(2)SeO(4)) is an inorganic Se compound used in human and animal nutrition that acts as precursor for selenoprotein synthesis. The organoselenium 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one (C(21)H(2)HOSe) is an α,ß-unsaturated ketone functionalized vinyl chalcogenide that has been found as a potential tool in organic synthesis. Adenosine deaminase (ADA) is an important enzyme in the degradation of adenine nucleotides. In this study, we investigated the in vitro effects of both Se compounds on ADA activity and cell viability in leukocyte suspension (LS) of healthy donors (n=12). We first observed an inhibition of ADA activity using 0.1 µM of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one, and an increase in cellular viability when 30 µM were used. However, we did not observe alterations in the presence of sodium selenate. Moreover, both Se compounds did not alter lactate dehydrogenase activity and thiobarbituric acid reactive substance levels. These results suggest that the inhibition of ADA activity caused by α,ß-unsaturated ketone may affect the adenosine levels in LS and modulate cell viability, attenuating conditions that involve the activation of the immune system.

Inhibition of creatine kinase activity by 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one in the cerebral cortex and cerebellum of young rats.

In the present study, we investigated the potential in vitro toxicity of the tellurium compound 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on creatine kinase activity in cerebral cortex and cerebellum of 30-day-old Wistar rats. First, enriched mitochondrial and cytosolic fractions from the two tissues were pre-incubated for 30 min in the presence or absence of 1, 5 or 20 microm of organotellurium and the creatine kinase activity was measured. The organochalcogen reduced creatine kinase activity in a concentration-dependent pattern in the two tissues studied. Furthermore, the enzyme activity was performed after pre-incubation for 30, 60 or 90 min in the presence of 5 microm of the organotellurium. The compound inhibited creatine kinase activity in a time-dependent way in the enriched mitochondrial fraction of both tissues, but not in the cytosolic fraction, indicating different mechanisms for the organochalcogen in the mitochondrial and in the cytosolic creatine kinase. Pre-incubation of tellurium compound with reduced glutathione suggests that creatine kinase activity inhibition might be caused by direct interaction with thiol groups or by oxidative stress. Our findings suggest that creatine kinase inhibition may be one of the mechanisms by which this organotellurium could cause toxicity to the rat brain.

Effect of acute administration of 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on oxidative stress in cerebral cortex, hippocampus, and cerebellum of rats.

Organotellurium compounds have been synthesized since 1840, but pharmacological and toxicological studies about them are still incipient. Therefore, the objective of this study was to verify the effect of acute administration of the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on some parameters of oxidative stress in the brain of 30-day-old rats. Animals were treated intraperitoneally with a single dose of the organotellurium (125, 250, or 500 µg/kg body weight) and sacrificed 60 min after the injection. The cerebral cortex, the hippocampus, and the cerebellum were dissected and homogenized in KCl. Afterward, thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD), nitric oxide (NO) formation, and hydroxyl radical production were measured in the brain. The organotellurium enhanced TBARS in the cerebral cortex and the hippocampus, and increased protein damage (carbonyl) in the cerebral cortex and the cerebellum. In contrast, the compound provoked a reduced loss of thiol groups measured by the sulfhydryl assay in all the tissues studied. Furthermore, the activity of the antioxidant enzyme CAT was reduced by the organochalcogen in the cerebral cortex and the cerebellum, and the activity of SOD was inhibited in all the brain tissues. Moreover, NO production was increased in the cerebral cortex and the cerebellum by this organochalcogen, and hydroxyl radical formation was also enhanced in the cerebral cortex. Our findings indicate that this organotellurium compound induces oxidative stress in the brain of rats, corroborating that this tissue is a potential target for organochalcogen action.

Effect of in vitro exposure of human serum to 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on oxidative stress.

The objective of this study was to verify the effect of the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on some parameters of oxidative stress in human serum. Serum of volunteers were incubated for 30 min in the presence or absence of 1, 10, or 30 microM of 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one and oxidative stress was measured. First, we tested the influence of the compound on 1,1-diphenyl-2-picrylhydrazyl (DPPH(*)) radical-scavenging and verified that the organotellurium did not have any antioxidant properties. The organochalcogen was capable to enhance TBARS but the compound was not able to alter carbonyl assay. Furthermore, the organochalcogen provoked a reduction of protein thiol groups measured by the sulfhydryl assay. Moreover, the organotellurium enhanced the activity of catalase and superoxide dismutase, inhibited the activity of glutathione peroxidase and did not modify the glutathione S-transferase activity. Furthermore, nitric oxide production and hydroxyl radical activity were not affected by the compound. Our findings showed that this organochalcogen induces oxidative stress in human serum, indicating that this compound is potentially toxic to human beings.

Effect of 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on oxidative stress in cerebral cortex of rats.

The objective of this study was to verify the effect of the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on some parameters of oxidative stress in the brain of 10-day-old rats. Cerebral cortex was incubated for 1h in the presence or absence of 1, 10 or 30 microM of 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one and thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), nitric oxide (NO) production and the release of the cytosolic enzyme lactate dehydrogenase (LDH) were measured. The organotellurium was not capable to alter TBARS and carbonyl assays. In contrast, the compound at 10 and 30 microM provoked a reduced of protein thiol groups measured by the sulfhydryl assay. Furthermore, the activity of the antioxidant enzyme CAT (10 and 30 microM) and GPx (1, 10 and 30 microM) was reduced by the organochalcogen. On the other hand, the activity of SOD and GST were enhanced respectively by 1, 10 and 30 microM of the compound. Furthermore, NO production was also increased by 30muM of this organochalcogen. Finally, we verified that the organotellurium was capable of enhance the LDH release at 30 microM concentration. Our findings indicate that this organotellurium compound induces in vitro oxidative stress in the cerebral cortex of rats being potentially toxic for the brain of rats.