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Archives of Toxicology (v.80, #2)
Excretion of mercapturic acids of acrylamide and glycidamide in human urine after single oral administration of deuterium-labelled acrylamide by Melanie I. Boettcher; Hermann M. Bolt; Hans Drexler; Jürgen Angerer (pp. 55-61).
We investigated the human metabolism of AA to the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) and N-(R/S)-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA) which are derived from AA itself and from its oxidative genotoxic metabolite glycidamide (GA), respectively. A healthy male volunteer received a single dose of about 1 mg deuterium-labelled acrylamide (d3-AA), representing 13 μg/kg body weight, in drinking water. Urine samples before dosing and within 46 h after the dose were analysed for d3-AAMA and d3-GAMA by LC-ESI-MS/MS. A first phase of increase in urinary concentration was found to last 18 h with a broad plateau between 8 and 18 h for AAMA, and 22 h for GAMA. Elimination half-lives of both AAMA and GAMA were estimated to be approximately 3.5 h for the first phase and more than 10 h up to few days for the second phase. Total recovery in urine after 24 h was about 51% as the sum of AAMA and GAMA and hereby well in accordance with former studies in rats. After 2 days AAMA, accounting for altogether 52% of the total AA dose, was the major metabolite of AA in humans. GAMA, accounting for 5%, appeared as a minor metabolite of AA. In humans we found a urinary ratio of 0.1 for GAMA/AAMA compared to previously reported values of 0.2 for rats and 0.5 for mice. Therefore, the metabolic fate of AA in humans was more similar to that in rats than in mice as already demonstrated in terms of the haemoglobin adducts. Consequently a genotoxic potency of AA mediated by GA could be supposed to be comparable in rats and humans.
Keywords: Acrylamide (AA); Glycidamide (GA); Metabolism; Human urine; Mercapturic acids
Excretion of mercapturic acids of acrylamide and glycidamide in human urine after single oral administration of deuterium-labelled acrylamide by Melanie I. Boettcher; Hermann M. Bolt; Hans Drexler; Jürgen Angerer (pp. 55-61).
We investigated the human metabolism of AA to the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) and N-(R/S)-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA) which are derived from AA itself and from its oxidative genotoxic metabolite glycidamide (GA), respectively. A healthy male volunteer received a single dose of about 1 mg deuterium-labelled acrylamide (d3-AA), representing 13 μg/kg body weight, in drinking water. Urine samples before dosing and within 46 h after the dose were analysed for d3-AAMA and d3-GAMA by LC-ESI-MS/MS. A first phase of increase in urinary concentration was found to last 18 h with a broad plateau between 8 and 18 h for AAMA, and 22 h for GAMA. Elimination half-lives of both AAMA and GAMA were estimated to be approximately 3.5 h for the first phase and more than 10 h up to few days for the second phase. Total recovery in urine after 24 h was about 51% as the sum of AAMA and GAMA and hereby well in accordance with former studies in rats. After 2 days AAMA, accounting for altogether 52% of the total AA dose, was the major metabolite of AA in humans. GAMA, accounting for 5%, appeared as a minor metabolite of AA. In humans we found a urinary ratio of 0.1 for GAMA/AAMA compared to previously reported values of 0.2 for rats and 0.5 for mice. Therefore, the metabolic fate of AA in humans was more similar to that in rats than in mice as already demonstrated in terms of the haemoglobin adducts. Consequently a genotoxic potency of AA mediated by GA could be supposed to be comparable in rats and humans.
Keywords: Acrylamide (AA); Glycidamide (GA); Metabolism; Human urine; Mercapturic acids
Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells by J. -M. Hwang; H. -C. Kuo; T. -H. Tseng; J. -Y. Liu; C. -Y. Chu (pp. 62-73).
Berberine, a main component of Coptidis Rhizoma, is a plant alkaloid with a long history of medicinal use in Chinese medicine. Berberine has indicated significant antimicrobial activity against a variety of organisms including bacteria, viruses, fungi. The mechanism by which berberine initiates apoptosis remains poorly understood. In the present study, we demonstrated that berberine exhibited significant cytotoxicity in hepatoma HepG2 cells but is ineffective in Chang liver cells. Herein we investigated cytotoxicity mechanism of berberine in HepG2 cells. The results showed that HepG2 cells underwent internucleosomal DNA fragmentation after 24-h treatment with berberine (50 μM). Moreover, berberine induced the activation of caspase-8 and −3, and caused the cleavage of poly ADP-ribose polymerase (PARP) and the cytochrome c release, whereas the expression of Bid and anti-apoptosis factor Bcl-XL were decreased markedly. The loss of mitochondrial membrane potential (Δ ψm) at 24 h and activation of Fas at 12 h were also seen in the berberine-treated HepG2 cells. These findings supported the fact that the inhibitors of caspases, DEVD-FMK, IETD-FMK and VAD-FMK, prevented apoptosis and restored the expression of Bcl-XL, Bcl-2 and Bid. These results indicated that the potential of anti-hepatoma activity of berberine may be mediated through a caspases-mitochondria-dependent pathway.
Keywords: Berberine; Hepatoma; Apoptosis
Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells by J. -M. Hwang; H. -C. Kuo; T. -H. Tseng; J. -Y. Liu; C. -Y. Chu (pp. 62-73).
Berberine, a main component of Coptidis Rhizoma, is a plant alkaloid with a long history of medicinal use in Chinese medicine. Berberine has indicated significant antimicrobial activity against a variety of organisms including bacteria, viruses, fungi. The mechanism by which berberine initiates apoptosis remains poorly understood. In the present study, we demonstrated that berberine exhibited significant cytotoxicity in hepatoma HepG2 cells but is ineffective in Chang liver cells. Herein we investigated cytotoxicity mechanism of berberine in HepG2 cells. The results showed that HepG2 cells underwent internucleosomal DNA fragmentation after 24-h treatment with berberine (50 μM). Moreover, berberine induced the activation of caspase-8 and −3, and caused the cleavage of poly ADP-ribose polymerase (PARP) and the cytochrome c release, whereas the expression of Bid and anti-apoptosis factor Bcl-XL were decreased markedly. The loss of mitochondrial membrane potential (Δ ψm) at 24 h and activation of Fas at 12 h were also seen in the berberine-treated HepG2 cells. These findings supported the fact that the inhibitors of caspases, DEVD-FMK, IETD-FMK and VAD-FMK, prevented apoptosis and restored the expression of Bcl-XL, Bcl-2 and Bid. These results indicated that the potential of anti-hepatoma activity of berberine may be mediated through a caspases-mitochondria-dependent pathway.
Keywords: Berberine; Hepatoma; Apoptosis
Evaluation of caspase-dependent apoptosis during fluoride-induced liver lesion in pigs by Xiu An Zhan; Min Wang; Zi Rong Xu; Wei Fen Li; Jian Xin Li (pp. 74-80).
Sixteen barrows (Duroc×Landrace×Yorkshire) were randomly divided into two groups, each consisting eight pigs. The groups received the same basal diet supplemented with 0 and 400 mg/kg fluoride, respectively. Histological examinations, including in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), Haematoxylin and Eosin staining (HE) and transmission electron microscopy observation, found apoptotic hepatocytes 50 days after additional 400 mg/kg fluoride treatment. The obvious DNA ladder and the significantly increased both hepatic caspase-9 and caspase-3 activity indicated that fluoride induced caspase-dependent apoptosis in vivo. In addition, serum glutamate pyruvate transaminase (GPT) activity and hepatic lipid peroxides (LPO) concentration was significantly increased. The activity of serum glutamate oxaloacetate transaminase (GOT) showed an increased trend. The results suggest that fluoride induces apoptosis by elevating the oxidative stress-induced lipid peroxidation, causing mitochondrial dysfunction and further activating caspase-9 and caspase-3.
Keywords: Fluoride; Apoptosis; Caspase-9; Caspase-3; LPO; GPT; GOT
Evaluation of caspase-dependent apoptosis during fluoride-induced liver lesion in pigs by Xiu An Zhan; Min Wang; Zi Rong Xu; Wei Fen Li; Jian Xin Li (pp. 74-80).
Sixteen barrows (Duroc×Landrace×Yorkshire) were randomly divided into two groups, each consisting eight pigs. The groups received the same basal diet supplemented with 0 and 400 mg/kg fluoride, respectively. Histological examinations, including in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), Haematoxylin and Eosin staining (HE) and transmission electron microscopy observation, found apoptotic hepatocytes 50 days after additional 400 mg/kg fluoride treatment. The obvious DNA ladder and the significantly increased both hepatic caspase-9 and caspase-3 activity indicated that fluoride induced caspase-dependent apoptosis in vivo. In addition, serum glutamate pyruvate transaminase (GPT) activity and hepatic lipid peroxides (LPO) concentration was significantly increased. The activity of serum glutamate oxaloacetate transaminase (GOT) showed an increased trend. The results suggest that fluoride induces apoptosis by elevating the oxidative stress-induced lipid peroxidation, causing mitochondrial dysfunction and further activating caspase-9 and caspase-3.
Keywords: Fluoride; Apoptosis; Caspase-9; Caspase-3; LPO; GPT; GOT
Effects of chronic exercise conditioning on thermal responses to lipopolysaccharide and turpentine abscess in female rats by Pamela Johnson Rowsey; Bonnie L. Metzger; John Carlson; Christopher J. Gordon (pp. 81-87).
Chronic exercise conditioning has been shown to alter basal thermoregulatory processes as well as the response to inflammatory agents. Two such agents, lipopolysaccharide (LPS) and turpentine (TPT) are inducers of fever in rats. LPS, given intraperitoneally (i.p.), involves a systemic inflammatory response whereas TPT given intramuscularly (i.m.) elicits a localized inflammation. We assessed if chronic exercise training in the rat would alter the thermoregulatory response to LPS and TPT. Core temperature (T c) and motor activity were monitored by radiotelemetry. Female Sprague Dawley rats were divided into two groups (trained and sedentary) and housed at an ambient temperature of 22°C. Animals voluntarily trained on running wheels for 8 weeks. In the first study, trained and sedentary female rats were injected i.p. with LPS (50 μg/kg) or an equal volume of 0.9% normal saline. In another study, trained and sedentary female rats were injected i.m. with TPT (10 μl)/rat or an equal volume of 0.9% normal saline. The time course of the LPS fever was very short compared to TPT. TPT injected animals displayed a smaller but more prolonged fever compared to LPS; however, training accentuated the febrile response to LPS (ΔT c=0.6°C in sedentary and 1.2°C in trained). Training had a slight suppression on TPT-induced fever during the daytime but had no effect on motor activity or nighttime T c. In contrast, exercise training led to a marked increase in the pyrogenic effects of LPS. We conclude that the effect of exercise training and source of infection (i.e., systemic versus localized in muscle) on fever is directly linked to type of pyrogenic agent.
Effects of chronic exercise conditioning on thermal responses to lipopolysaccharide and turpentine abscess in female rats by Pamela Johnson Rowsey; Bonnie L. Metzger; John Carlson; Christopher J. Gordon (pp. 81-87).
Chronic exercise conditioning has been shown to alter basal thermoregulatory processes as well as the response to inflammatory agents. Two such agents, lipopolysaccharide (LPS) and turpentine (TPT) are inducers of fever in rats. LPS, given intraperitoneally (i.p.), involves a systemic inflammatory response whereas TPT given intramuscularly (i.m.) elicits a localized inflammation. We assessed if chronic exercise training in the rat would alter the thermoregulatory response to LPS and TPT. Core temperature (T c) and motor activity were monitored by radiotelemetry. Female Sprague Dawley rats were divided into two groups (trained and sedentary) and housed at an ambient temperature of 22°C. Animals voluntarily trained on running wheels for 8 weeks. In the first study, trained and sedentary female rats were injected i.p. with LPS (50 μg/kg) or an equal volume of 0.9% normal saline. In another study, trained and sedentary female rats were injected i.m. with TPT (10 μl)/rat or an equal volume of 0.9% normal saline. The time course of the LPS fever was very short compared to TPT. TPT injected animals displayed a smaller but more prolonged fever compared to LPS; however, training accentuated the febrile response to LPS (ΔT c=0.6°C in sedentary and 1.2°C in trained). Training had a slight suppression on TPT-induced fever during the daytime but had no effect on motor activity or nighttime T c. In contrast, exercise training led to a marked increase in the pyrogenic effects of LPS. We conclude that the effect of exercise training and source of infection (i.e., systemic versus localized in muscle) on fever is directly linked to type of pyrogenic agent.
Mechanisms of rolipram-induced increase in the incidence of mammary adenocarcinoma: histopathological study of a 104-week oral carcinogenicity study in female Sprague-Dawley rats by Shoji Nishiyama; Masahiko Okudaira; Noboru Saito (pp. 88-97).
The present study was carried out to elucidate the mechanisms behind an increase in the incidence of malignant or multiple mammary tumors as a result of oral administration of rolipram in a 104-week carcinogenicity study. The organs and tissues of Sprague-Dawley (SD) rats of both sexes, which had been subjected to a 104-week oral carcinogenicity study at doses of 0.2, 0.6 and 2.0 mg/kg, were examined. No treatment-related effects were seen in males; however, in females, there was a significant increase in the number of malignant or multiple mammary tumor bearers at a dose of 2.0 mg/kg. No other target organs were identified and the incidence of other tumor types were within the female control range. To clarify the mechanisms behind a rolipram-induced increase in the incidence of mammary adenocarcinoma at time points earlier than 104 weeks, the hormonal changes associated with pituitary adenoma were identified, and estrous cycling in the ovary, uterus, and vagina were examined in female rats treated with rolipram for 52 weeks. The plasma prolactin (PRL) concentration in all female groups exceeded the control value at Week 52, and all these differences were statistically significant. There was also a dose-dependent relationship with PRL-producing pituitary adenomas. Changes in estrous cycling in the uterus and vagina and a decrease in the size and number of corpora lutea in the ovaries of female rats treated with rolipram at 2.0 mg/kg for 52 weeks indicated that an increase in the estrus phase of the cycle corresponded to a marked decrease in the diestrus phase, which might result from the increased plasma estrogen concentration. Together, all of the above mentioned data suggest that rolipram not only stimulates an increase in the number and size of PRL adenomas in the pituitary gland but also in the estrus phase of the estrous cycle. These events might cause progression of the mammary gland tissues from hyperplasia to carcinoma.
Keywords: Rolipram; Prolactin; Estrous cycling; Mammary adenocarcinoma; Carcinogenicity study
Mechanisms of rolipram-induced increase in the incidence of mammary adenocarcinoma: histopathological study of a 104-week oral carcinogenicity study in female Sprague-Dawley rats by Shoji Nishiyama; Masahiko Okudaira; Noboru Saito (pp. 88-97).
The present study was carried out to elucidate the mechanisms behind an increase in the incidence of malignant or multiple mammary tumors as a result of oral administration of rolipram in a 104-week carcinogenicity study. The organs and tissues of Sprague-Dawley (SD) rats of both sexes, which had been subjected to a 104-week oral carcinogenicity study at doses of 0.2, 0.6 and 2.0 mg/kg, were examined. No treatment-related effects were seen in males; however, in females, there was a significant increase in the number of malignant or multiple mammary tumor bearers at a dose of 2.0 mg/kg. No other target organs were identified and the incidence of other tumor types were within the female control range. To clarify the mechanisms behind a rolipram-induced increase in the incidence of mammary adenocarcinoma at time points earlier than 104 weeks, the hormonal changes associated with pituitary adenoma were identified, and estrous cycling in the ovary, uterus, and vagina were examined in female rats treated with rolipram for 52 weeks. The plasma prolactin (PRL) concentration in all female groups exceeded the control value at Week 52, and all these differences were statistically significant. There was also a dose-dependent relationship with PRL-producing pituitary adenomas. Changes in estrous cycling in the uterus and vagina and a decrease in the size and number of corpora lutea in the ovaries of female rats treated with rolipram at 2.0 mg/kg for 52 weeks indicated that an increase in the estrus phase of the cycle corresponded to a marked decrease in the diestrus phase, which might result from the increased plasma estrogen concentration. Together, all of the above mentioned data suggest that rolipram not only stimulates an increase in the number and size of PRL adenomas in the pituitary gland but also in the estrus phase of the estrous cycle. These events might cause progression of the mammary gland tissues from hyperplasia to carcinoma.
Keywords: Rolipram; Prolactin; Estrous cycling; Mammary adenocarcinoma; Carcinogenicity study
Cellular uptake and cytotoxic potential of respirable bentonite particles with different quartz contents and chemical modifications in human lung fibroblasts by Stefan Geh; Raif Yücel; Rodger Duffin; Catrin Albrecht; Paul J. A. Borm; Lorenz Armbruster; Monika Raulf-Heimsoth; Thomas Brüning; Eik Hoffmann; Albert W. Rettenmeier; Elke Dopp (pp. 98-106).
Considering the biological reactivity of pure quartz in lung cells, there is a strong interest to clarify the cellular effects of respirable siliceous dusts, like bentonites. In the present study, we investigated the cellular uptake and the cytotoxic potential of bentonite particles (Ø< 10 μm) with an α-quartz content of up to 6% and different chemical modifications (activation: alkaline, acidic, organic) in human lung fibroblasts (IMR90). Additionally, the ability of the particles to induce apoptosis in IMR90-cells and the hemolytic activity was tested. All bentonite samples were tested for endotoxins with the in vitro-Pyrogen test and were found to be negative. Cellular uptake of particles by IMR90-cells was studied by transmission electron microscopy (TEM). Cytotoxicity was analyzed in IMR90-cells by determination of viable cells using flow cytometry and by measuring of the cell respiratory activity. Induced apoptotic cells were detected by AnnexinV/Propidiumiodide-staining and gel electrophoresis. Our results demonstrate that activated bentonite particles are better taken up by IMR90-cells than untreated (native) bentonite particles. Also, activated bentonite particles with a quartz content of 5–6% were more cytotoxic than untreated bentonites or bentonites with a quartz content lower than 4%. The bentonite samples induced necrotic as well as apoptotic cell death. In general, bentonites showed a high membrane-damaging potential shown as hemolytic activity in human erythrocytes. We conclude that cellular effects of bentonite particles in human lung cells are enhanced after chemical treatment of the particles. The cytotoxic potential of the different bentonites is primarily characterized by a strong lysis of the cell membrane.
Keywords: Bentonite; Quartz; Cellular uptake; Cytotoxicity; Apoptosis; Human lung fibroblasts
Cellular uptake and cytotoxic potential of respirable bentonite particles with different quartz contents and chemical modifications in human lung fibroblasts by Stefan Geh; Raif Yücel; Rodger Duffin; Catrin Albrecht; Paul J. A. Borm; Lorenz Armbruster; Monika Raulf-Heimsoth; Thomas Brüning; Eik Hoffmann; Albert W. Rettenmeier; Elke Dopp (pp. 98-106).
Considering the biological reactivity of pure quartz in lung cells, there is a strong interest to clarify the cellular effects of respirable siliceous dusts, like bentonites. In the present study, we investigated the cellular uptake and the cytotoxic potential of bentonite particles (Ø< 10 μm) with an α-quartz content of up to 6% and different chemical modifications (activation: alkaline, acidic, organic) in human lung fibroblasts (IMR90). Additionally, the ability of the particles to induce apoptosis in IMR90-cells and the hemolytic activity was tested. All bentonite samples were tested for endotoxins with the in vitro-Pyrogen test and were found to be negative. Cellular uptake of particles by IMR90-cells was studied by transmission electron microscopy (TEM). Cytotoxicity was analyzed in IMR90-cells by determination of viable cells using flow cytometry and by measuring of the cell respiratory activity. Induced apoptotic cells were detected by AnnexinV/Propidiumiodide-staining and gel electrophoresis. Our results demonstrate that activated bentonite particles are better taken up by IMR90-cells than untreated (native) bentonite particles. Also, activated bentonite particles with a quartz content of 5–6% were more cytotoxic than untreated bentonites or bentonites with a quartz content lower than 4%. The bentonite samples induced necrotic as well as apoptotic cell death. In general, bentonites showed a high membrane-damaging potential shown as hemolytic activity in human erythrocytes. We conclude that cellular effects of bentonite particles in human lung cells are enhanced after chemical treatment of the particles. The cytotoxic potential of the different bentonites is primarily characterized by a strong lysis of the cell membrane.
Keywords: Bentonite; Quartz; Cellular uptake; Cytotoxicity; Apoptosis; Human lung fibroblasts
Diminished embryonic movements of developing embryo by direct exposure of sidestream whole smoke solutions by Sohail Ejaz; Lim Chae Woong (pp. 107-114).
Embryonic movements (EM) are considered to be the first sign of life and cigarette smoking during pregnancy has been linked to affect EM. Exposure to sidestream smoke, produced from the emissions of a smoldering cigarette, may result in poor pregnancy outcome and increased risk of serious perinatal morbidity and mortality. In this study, the chicken embryo bioassay was used to systematically assess the effects of short-term exposure to sidestream whole smoke solutions (SSWSS) on EM, recorded in real time by a video camera for 60 min and each EM was counted for every 3-min interval. Application of different types of SSWSS to the embryos caused significant changes in all types of EM from 15 to 18 min of recording time. Extensive reduction (P<0.001) and some time complete stoppage of swing-like movements and whole-body movements were observed in almost all treated embryos. Our data clearly link between exposure of SSWSS and substantial decrease in EM. It is unclear whether nicotine and/or other ingredients present in sidestream smoke are responsible for these alterations in EM. This article provides an outline of the relevance of SSWSS on EM for evolutionary developmental biology and this assay can be used to investigate the complex mixtures with regard to their effects on EM.
Keywords: Embryonic movements; Smoking; Chicken embryo; Sidestream whole smoke solutions
Diminished embryonic movements of developing embryo by direct exposure of sidestream whole smoke solutions by Sohail Ejaz; Lim Chae Woong (pp. 107-114).
Embryonic movements (EM) are considered to be the first sign of life and cigarette smoking during pregnancy has been linked to affect EM. Exposure to sidestream smoke, produced from the emissions of a smoldering cigarette, may result in poor pregnancy outcome and increased risk of serious perinatal morbidity and mortality. In this study, the chicken embryo bioassay was used to systematically assess the effects of short-term exposure to sidestream whole smoke solutions (SSWSS) on EM, recorded in real time by a video camera for 60 min and each EM was counted for every 3-min interval. Application of different types of SSWSS to the embryos caused significant changes in all types of EM from 15 to 18 min of recording time. Extensive reduction (P<0.001) and some time complete stoppage of swing-like movements and whole-body movements were observed in almost all treated embryos. Our data clearly link between exposure of SSWSS and substantial decrease in EM. It is unclear whether nicotine and/or other ingredients present in sidestream smoke are responsible for these alterations in EM. This article provides an outline of the relevance of SSWSS on EM for evolutionary developmental biology and this assay can be used to investigate the complex mixtures with regard to their effects on EM.
Keywords: Embryonic movements; Smoking; Chicken embryo; Sidestream whole smoke solutions
Protective effect of lipoic acid on micronuclei induction by cyclophosphamide by Elangovan Selvakumar; Chidambaram Prahalathan; Periyasamy Thandavan Sudharsan; Palaninathan Varalakshmi (pp. 115-119).
The present study investigated the protective efficacy of DL-α-lipoic acid on the cyclophosphamide (CP)-induced clastogenicity using the in vivo micronucleus assay. Male Wistar rats of 140 ± 20 g were categorized into eight groups. Five groups were administered CP (40 mg/kg body weight, intraperitonealy) to induce genotoxicity; four of these groups received a single intraperitoneal injection of lipoic acid at a dose of either 100 or 200 mg/kg body weight, and either 30 or 60 min prior to CP administration. A vehicle-treated control group and lipoic acid control groups were also included. The number of micronucleated polychromatic erythrocytes (MNPCEs) was determined at 24 h after CP administration. In rats injected with CP, the frequency of MNPCEs in bone marrow and peripheral blood was increased significantly in comparison with the controls, and in rats treated with lipoic acid and CP, the number of MNPCEs was decreased significantly in comparison to those given CP alone. The chemoprotective effect was found to be stronger after the administration of lipoic acid at a dose of 200 mg/kg body weight than 100 mg/kg body weight dosage, indicating the dose-dependent protective effect of lipoic acid. However, the protection by lipoic acid was not dependent on the time intervals between lipoic acid and CP administration. Our results illustrate the protective effect of lipoic acid on the in vivo clastogenicity induced by CP.
Keywords: Cyclophosphamide; Lipoic acid; Micronuclei; Bone marrow; Peripheral blood
Protective effect of lipoic acid on micronuclei induction by cyclophosphamide by Elangovan Selvakumar; Chidambaram Prahalathan; Periyasamy Thandavan Sudharsan; Palaninathan Varalakshmi (pp. 115-119).
The present study investigated the protective efficacy of DL-α-lipoic acid on the cyclophosphamide (CP)-induced clastogenicity using the in vivo micronucleus assay. Male Wistar rats of 140 ± 20 g were categorized into eight groups. Five groups were administered CP (40 mg/kg body weight, intraperitonealy) to induce genotoxicity; four of these groups received a single intraperitoneal injection of lipoic acid at a dose of either 100 or 200 mg/kg body weight, and either 30 or 60 min prior to CP administration. A vehicle-treated control group and lipoic acid control groups were also included. The number of micronucleated polychromatic erythrocytes (MNPCEs) was determined at 24 h after CP administration. In rats injected with CP, the frequency of MNPCEs in bone marrow and peripheral blood was increased significantly in comparison with the controls, and in rats treated with lipoic acid and CP, the number of MNPCEs was decreased significantly in comparison to those given CP alone. The chemoprotective effect was found to be stronger after the administration of lipoic acid at a dose of 200 mg/kg body weight than 100 mg/kg body weight dosage, indicating the dose-dependent protective effect of lipoic acid. However, the protection by lipoic acid was not dependent on the time intervals between lipoic acid and CP administration. Our results illustrate the protective effect of lipoic acid on the in vivo clastogenicity induced by CP.
Keywords: Cyclophosphamide; Lipoic acid; Micronuclei; Bone marrow; Peripheral blood