RESUMEN
The metallothionein family is a class of low-molecular-weight, cysteine-rich proteins with high affinity for metal ions. Four major isoforms (metallothionein-1, -2, -3, and -4) have been identified in mammals, involved in many pathophysiological processes, including metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, drug and radiotherapy resistance and several aspects of the carcinogenic process. In the present review we examine the expression of metallothionein in different human tumours and its correlation with histopathological variables, tumour cell proliferation or apoptosis, resistance to radiation or chemotherapy, patient survival and prognosis. A variable profile of metallothionein and its isoforms' expression has been observed in different cancer types. Although metallothionein expression has been implicated in carcinogenic evolution, its use as a marker of tumour differentiation, cell proliferation and prognosis predictor remains unclear. Detailed studies focused on the expression of metallothionein isoforms and isotypes in different tumour types could elucidate the role of this group of proteins in the carcinogenic process, delineating its possible clinical significance for the management of patients.
Asunto(s)
Metalotioneína/metabolismo , Neoplasias/metabolismo , Apoptosis , Proliferación Celular , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Humanos , Neoplasias/patología , Neoplasias/terapia , Isoformas de Proteínas/metabolismo , Tolerancia a RadiaciónRESUMEN
The metallothionein (MT) family is a class of low molecular weight, intracellular and cysteine-rich proteins presenting high affinity for metal ions. Although the members of this family were discovered nearly 40 years ago, their functional significance remains obscure. Four major MT isoforms, MT-1, MT-2, MT-3 and MT-4, have been identified in mammals. MTs are involved in many pathophysiological processes such as metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, chemoresistance and radiotherapy resistance. MT isoforms have been shown to be involved in several aspects of the carcinogenic process, cancer development and progression. MT expression has been implicated as a transient response to any form of stress or injury providing cytoprotective action. Although MT participates in the carcinogenic process, its use as a potential marker of tumor differentiation or cell proliferation, or as a predictor of poor prognosis remains unclear. In the present review the involvement of MT in defense mechanisms to toxicity and in carcinogenicity is discussed.
Asunto(s)
Metalotioneína/fisiología , Animales , Apoptosis , Diferenciación Celular , División Celular , Cisteína/química , Progresión de la Enfermedad , Resistencia a Medicamentos , Epítopos , Radicales Libres , Humanos , Iones , Metalotioneína/genética , Neoplasias/metabolismo , Oxígeno/metabolismo , Pronóstico , Isoformas de ProteínasRESUMEN
Metallothioneins (MTs), are low molecular weight proteins, mainly implicated in metal ion detoxification. In the present study, we investigated the expression of hepatic MT in a rat model of injury and regeneration, induced by carbon tetrachloride (CCl(4)) administration. A single intraperitoneal injection of 1 ml CCl(4)/kg body weight was performed in male Wistar rats, killed at different time points post-administration. The enzymatic activities of aspartate and alanine aminotransferases in serum were determined, in addition to the liver histological findings, to estimate hepatotoxicity. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of thymidine kinase in liver tissue and the assessment of the mitotic index in hepatocytes, were used as indices of regeneration. MT was detected immunohistochemically in liver tissue sections. CCl(4) administration caused severe hepatic injury, followed by regeneration. MT expression became prominent as early as 12 h after the administration of CCl(4), in the nuclei of hepatocytes, while at 24 and 36 h intense cytoplasmic staining for MT appeared in the hepatocytes in the vicinity of necrotic areas. The peak of hepatocyte proliferative capacity, occurring at 48 h post-CCl(4) administration coincides with the maximum nuclear and cytoplasmic MT expression. At further time points MT expression presented a decreasing trend. Induction of MT expression was observed in the liver after a single administration of CCl(4), being more prominent at the time of maximum hepatocellular proliferation, participating actively in the replication of hepatocytes.
Asunto(s)
Intoxicación por Tetracloruro de Carbono/metabolismo , Regeneración Hepática , Hígado/efectos de los fármacos , Hígado/metabolismo , Metalotioneína/biosíntesis , Animales , ADN/biosíntesis , Inmunohistoquímica , Inyecciones Intraperitoneales , Hígado/patología , Masculino , Metalotioneína/metabolismo , Ratas , Ratas Wistar , Timidina Quinasa/metabolismoRESUMEN
Metallothioneins (MT), a group of ubiquitous low molecular weight proteins, implicated primarily in metal ion detoxification, are known to be expressed during hepatocellular proliferation after partial hepatectomy in rats. In the present study, we investigated the expression of MT in a rat model of liver injury and regeneration, induced by intraperitoneal administration of thioacetamide (TAA). The animals were killed at 0, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 hours after TAA administration. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of thymidine kinase, and the assessment of the mitotic index in hepatocytes were used as indices of liver regeneration. Liver MTs were detected immunohistochemically. TAA administration caused severe hepatic injury, followed by regeneration. MT expression became prominent in hepatocytes as early as 12 hours post-TAA administration. At 24 and 36 hours post-TAA administration intense nuclear and cytoplasmic staining of hepatocytes was found in the vicinity of necrotic areas. The maximal nuclear and cytoplasmic MT expression coincides with the peak of hepatocyte proliferative capacity, occurring at 48 and 60 hours post-TAA administration. MT expression correlated positively with the Zn content of liver tissue, but negatively with serum one, at the time of maximum hepatocyte proliferative capacity. This study suggests that MT participates in hepatocyte replication after toxin-induced liver injury.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Regeneración Hepática/efectos de los fármacos , Hígado/metabolismo , Metalotioneína/biosíntesis , Tioacetamida/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , ADN/biosíntesis , ADN/efectos de los fármacos , Inyecciones Intraperitoneales , Hígado/efectos de los fármacos , Hígado/patología , Regeneración Hepática/fisiología , Masculino , Índice Mitótico/efectos de los fármacos , Ratas , Ratas Wistar , Tioacetamida/administración & dosificación , Timidina/metabolismo , Timidina Quinasa/metabolismo , Zinc/sangreRESUMEN
Metallothioneins (MT) are cytosolic proteins rich in cysteine which play a physiological role in metal ion homeostasis. Heat shock proteins (HSPs) are expressed in various organs in response to different stress stimuli. The purpose of the present study was to examine the intrahepatic distribution of MT and HSP-27, -70 and -90 in two different experimental models of acute liver injury and regeneration, induced by either thioacetamide, or carbon tetrachloride administration in male Wistar rats. Toxicological endpoints and markers of hepatocellular regeneration were assessed at various time points following toxin administration. The enzymatic activities of aspartate and alanine aminotransferases in serum, and histological findings in the liver were used to estimate toxin-induced injury. Tritiated thymidine incorporation into hepatic DNA, liver thymidine kinase activity and hepatocyte mitotic index were used to estimate liver regeneration. MT and HSPs were detected immunohistochemically. At the time of maximum liver injury, moderate MT and intense HSPs expression was prominent in hepatocytes in the vicinity of necrotic areas. At the time of maximum hepatocellular proliferation, intense MT and HSP-90 staining was evident in all hepatocytes, while at the same time, mild HSP-27 and HSP-70 immunoreactivity was noted. Our findings indicate that the differential distribution of MT and HSPs in the liver after toxin-induced injury, in common with the observed pattern of staining, reflect liver proliferating capacity.
Asunto(s)
Tetracloruro de Carbono/toxicidad , Proteínas de Choque Térmico/metabolismo , Regeneración Hepática , Hígado/efectos de los fármacos , Metalotioneína/metabolismo , Tioacetamida/toxicidad , Animales , Inmunohistoquímica , Hígado/fisiología , Masculino , Ratas , Ratas WistarRESUMEN
It has been shown recently that granulocyte colony-stimulating factor (G-CSF) accelerates and enhances the hepatocyte proliferative capacity of partially hepatectomized rats. In the present study, we investigated the effect of G-CSF administration in a rat model of liver injury and regeneration, induced by thioacetamide (TAA) injection. TAA (300 mg/kg body weight) was injected intraperitoneally in male Wistar rats, and this was followed by administration of either saline (group A) or G-CSF at a dose of 150 microg/kg body weight (group B), 24 hr later. The animals were killed at different time points after TAA treatment and the rate of tritiated thymidine incorporation into hepatic DNA, the activity of the enzyme thymidine kinase (EC 2.7.1.21) in the liver, and the assessment of the mitotic index of hepatocytes, were employed to estimate liver regeneration. The administration of TAA caused severe hepatic injury, recognized histopathologically and by the raised activities of the serum hepatic enzymes aspartate and alanine aminotransferases. The hepatic injury, which peaked 36 hr after TAA injection, was followed by a regenerative process of hepatocytes presenting peaks at time points of 48 and 60 hr (group A). The administration of G-CSF 24 hr after the injection of TAA (group B) caused a statistically significantly increase in the hepatocyte proliferation indices examined (P < 0.001), compared to those found in group A at the same time points. It was concluded that G-CSF administration enhanced the hepatocyte proliferative capacity in this model of liver injury induced by TAA administration.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Factor Estimulante de Colonias de Granulocitos/farmacología , Regeneración Hepática/efectos de los fármacos , Tioacetamida , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/patología , Hígado/fisiología , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
AIMS/BACKGROUND: Hepatic stimulator substance (HSS) is a known hepatic growth factor which appears to be organ-specific but species non-specific. We have recently shown that the administration of HSS enhanced hepatocyte proliferation occurring due to thioacetamide (TAA)-induced liver injury in rats (Theocharis SE, et al., Scand J Gastroenterol 1998; 33: 656-63). In the present study, we examined the activity of the endogenously produced HSS in the liver of TAA administered rats during injury and regeneration. METHODS: TAA at a dose of 300 mg/kg of body weight was injected intraperitoneally in male Wistar rats. The animals were sacrificed at 0, 12, 24, 36, 48, 60 and 72 h after TAA administration. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase and the assessment of mitotic index in hepatocytes were used to estimate liver regeneration. HSS extract was obtained from the livers of TAA-treated rats, sacrificed at the above mentioned time points. This HSS extract was injected in 34% partially hepatectomized rats, to assess its activity. The ability of the injected HSS extract to increase hepatocellular proliferation over that normally occurring 24 h following 34% partial hepatectomy was used to express the activity of HSS by determining the above mentioned indices of liver regeneration. RESULTS: The administration of TAA caused severe hepatic injury recognized histopathologically as well as by the increased activities of serum hepatic enzymes aspartate and alanine aminotrasferases. The hepatic injury, which peaked at 24 and 36 h post-TAA treatment (p<0.001), was followed by hepatocyte proliferation, presenting peaks at 48 and 60 h (p<0.001). The activity of the endogenously produced HSS from livers of TAA-treated rats increased at 36 h after TAA administration as well as being highly expressed at 48 and 60 h thus coinciding with the peak of hepatocyte proliferation. At other time points, HSS activity was decreased. CONCLUSIONS: The observed variations of HSS activity in rat liver suggest active participation of this growth factor in hepatocyte replication which follows toxin-induced liver injury as a repair mechanism process.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Sustancias de Crecimiento/metabolismo , Regeneración Hepática/fisiología , Hígado/metabolismo , Péptidos/metabolismo , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , ADN/biosíntesis , Sustancias de Crecimiento/farmacología , Hepatectomía , Inyecciones Intraperitoneales , Péptidos y Proteínas de Señalización Intercelular , Hígado/efectos de los fármacos , Masculino , Índice Mitótico/efectos de los fármacos , Péptidos/farmacología , Ratas , Ratas Wistar , Tioacetamida/toxicidad , Timidina/metabolismo , Timidina Quinasa/metabolismoRESUMEN
The liver is of central importance in the metabolism of essential and toxic metals such as cadmium. Cadmium pretreatment suppressed the liver regenerative response to partial hepatectomy, due to the inhibition of the enzymatic activity of thymidine kinase. Exogenous putrescine administration has been reported to stimulate liver regeneration in animal models of acute liver failure. The purpose of this study was to document whether the administration of this polyamine enhances the impaired regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. The intraperitoneal administration of putrescine (1 or 10 mg/kg body weight), at the time of surgery and at 4 and 8 hr postoperatively partly restored the suppressed hepatocyte deoxyribonucleic acid (DNA) biosynthesis and thymidine kinase activity in cadmium-pretreated partially hepatectomized rats. Mitotic activity and the percentage of hepatocytes positive for proliferating cell nuclear antigen nuclei were in accordance with the liver proliferative status. Our results showed that exogenous putrescine administration is able to improve diminished liver regeneration after partial hepatectomy in this animal model of acute hepatic injury.
Asunto(s)
Cadmio/farmacología , Regeneración Hepática/efectos de los fármacos , Putrescina/farmacología , Animales , División Celular , ADN/biosíntesis , Hepatectomía , Hígado/citología , Hígado/metabolismo , Masculino , Antígeno Nuclear de Célula en Proliferación/análisis , Ratas , Ratas Wistar , Timidina Quinasa/antagonistas & inhibidores , Timidina Quinasa/metabolismoRESUMEN
BACKGROUND: Hepatic stimulator substance (HSS) is a known hepatic growth factor that appears to be organ-specific but species-nonspecific. In the present study we investigated the effect of HSS administration in a rat model of liver injury and regeneration induced by thioacetamide (TAA) injection. METHODS: TAA (300 mg/kg body weight) was injected intraperitoneally in male Wistar rats (group I). HSS (50 mg protein/kg body weight) was administered intraperitoneally either at 24 h (group II) or at 36 h (group III) after TAA treatment. The animals were killed at different time points after TAA injection, and the rate of tritiated thymidine incorporation into hepatic DNA, the activity of the enzyme thymidine kinase in liver, and the assessment of the mitotic index in hepatocytes were used to estimate liver regeneration. RESULTS: The administration of TAA caused severe hepatic injury recognized histopathologically and by increased activities of the serum hepatic enzymes aspartate and alanine aminotransferases. The hepatic injury, which peaked at 24 h and 36 h after TAA injection, was followed by a regenerative process of hepatocytes which presented peaks after 48 h and 60 h (group I). The regenerative process of hepatocytes remained unaffected when HSS was administered 24 h after the injection of TAA (group II). In the case of HSS administration 36 h after the injection of TAA (group III) the examined indices of hepatocyte proliferation were statistically significantly increased at 48 h (P < 0.001), compared with those observed in group I. CONCLUSIONS: The administration of HSS enhanced the hepatocyte proliferative capacity, induced by TAA treatment, depending on the time of its administration.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Sustancias de Crecimiento/farmacología , Regeneración Hepática/efectos de los fármacos , Mitógenos/farmacología , Péptidos/farmacología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Carcinógenos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Péptidos y Proteínas de Señalización Intercelular , Regeneración Hepática/fisiología , Masculino , Ratas , Ratas Wistar , Tioacetamida , Factores de TiempoRESUMEN
The purpose of the present study was to delineate the effect of interferon-alpha2b (IFN-alpha2b) administration on the liver regenerative capacity after partial hepatectomy in rats. The administration of IFN-alpha2b simultaneously with partial hepatectomy did not affect hepatic proliferation in a statistically significant manner. When IFN-alpha2b was administered either 2 or 12 hr postoperatively, an inhibition of hepatocyte proliferation was observed 24 hr postoperatively, while at further time intervals up to 48 hr, DNA synthesis remained similar to that observed in the simply partially hepatectomized rats. The enzyme thymidine kinase (TK), has been implicated in the suppression of proliferation in interferon-treated cell cultures. In all IFN-alpha2b-treated groups of rats, alterations of TK activity were observed without being correlated to the liver regenerative status. Additionally, the administration of the polyamine putrescine in partially hepatectomized rats treated at the time of surgery with IFN strongly enhanced TK activity, but did not affect DNA biosynthesis. In the above-mentioned in vivo model of controlled cellular proliferation, the administration of IFN-alpha2b affected the rate of hepatocyte proliferation depending on the time of its administration; this effect was not correlated to the enzymatic activity of TK, as inhibited TK activity is responsible for the suppressed DNA synthesis in in vitro systems.
Asunto(s)
Interferón-alfa/farmacología , Regeneración Hepática/efectos de los fármacos , Animales , División Celular/efectos de los fármacos , ADN/biosíntesis , Hepatectomía , Interferón alfa-2 , Hígado/enzimología , Masculino , Putrescina/farmacología , Ratas , Ratas Wistar , Proteínas Recombinantes , Timidina Quinasa/metabolismo , Factores de TiempoRESUMEN
1. The purpose of this study was to determine whether the commercially available forms of granulocyte-colony-stimulating factor exert the same beneficial effect on hepatic regeneration after 70% partial hepatectomy in rats. Adult male Wistar rats received either the two commercially available forms of granulocyte-colony-stimulating factor (Filgrastim or Lenograstim), or saline, simultaneously with partial hepatectomy. Hepatic regeneration was documented by determining [3H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, mitotic index and proliferating cell nuclear antigen immunostaining, at various time points after partial hepatectomy. 2. DNA biosynthesis, liver thymidine kinase activity and mitotic index of hepatocytes were not only enhanced (P < 0.001) in rats that received 150 micrograms of Filgrastim or Lenograstim/kg of body weight, but occurred earlier than in saline-treated partially hepatectomized rats. The administration of both forms of granulocyte-colony-stimulating factor, at the dose of 15 micrograms/kg of body weight, did not affect liver proliferative capacity, compared with observations in simply partially hepatectomized rats. High mitotic and proliferating cell nuclear antigen indices appeared earlier than those estimated in simply partially hepatectomized rats, when 150 micrograms of Filgrastim or Lenograstim/kg of body weight were administered. 3. These findings suggest that both pharmacologically available forms of granulocyte-colony-stimulating factor at a dose of 150 micrograms/kg of body weight are able to augment liver regenerative capacity, to the same extent, in this animal model of controlled hepatic proliferation.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Regeneración Hepática/efectos de los fármacos , Adyuvantes Inmunológicos/farmacología , Animales , ADN/biosíntesis , Filgrastim , Inmunohistoquímica , Lenograstim , Hígado/metabolismo , Masculino , Índice Mitótico , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacología , Timidina/metabolismo , Timidina Quinasa/metabolismoRESUMEN
OBJECTIVE: To document whether the administration of granulocyte colony-stimulating factor (G-CSF) enhances the impaired regenerative response of hepatocytes to partial hepatectomy (PH), in cadmium-pretreated partially hepatectomized rats. MATERIALS AND METHODS: Rats were injected intraperioneally with 2.5 mg CdCl2/kg body weight, 24h before PH. G-CSF (1500 or 150 micrograms/kg body weight) or saline was administered intraperitoneally in cadmium-pretreated partially hepatectomized rats at the same time as PH. The liver regenerative process was estimated 24h after PH. [3H] thymidine incorporation into liver DNA, liver thymidine kinase (TK) activity, mitotic index and proliferating cell nuclear antigen (PCNA) immunostaining were used as indices of hepatocyte proliferation. RESULTS: G-CSF administration in cadmium-pretreated partially hepatectomized rats restored the suppressed DNA biosynthesis and TK activity (P < 0.001), to levels similar to those found in rats that were partially hepatectomized only. The mitotic index and the percentage of PCNA positive nuclei in hepatocytes were also enhanced in G-CSF administered cadmium-pretreated partially hepatectomized groups of rats. CONCLUSION: The administration of G-CSF triggers events that restore the impaired liver regeneration in this model of reduced hepatocyte proliferation.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Regeneración Hepática/efectos de los fármacos , Hígado/citología , Animales , Cadmio/toxicidad , Modelos Animales de Enfermedad , Hepatectomía , Hígado/efectos de los fármacos , Hígado/fisiología , Masculino , Índice Mitótico , Ratas , Ratas WistarRESUMEN
The liver is of central importance in the metabolism of essential and toxic metals such as cadmium (Cd). Cd pretreatment suppressed the regenerative capacity of hepatocytes, which normally occurs 24 hr after partial hepatectomy, due to the inhibition of the activity of the enzyme thymidine kinase. The effect of hepatic stimulator substance (HSS) administration (10, 20, and 40 mg protein/kg body weight) on hepatocyte proliferation was investigated in Cd-pretreated partially hepatectomized rats. HSS administration partly restored the suppressed hepatocyte DNA biosynthesis in Cd-pretreated partially hepatectomized rats. The hepatocyte mitotic activity and the percentage of proliferating cell nuclear antigen-positive nuclei were in accordance with the liver proliferative status. The administration of HSS did not affect in a statistically significant manner the activity of the enzyme thymidine kinase in Cd-pretreated partially hepatectomized rats. It is suggested that the administration of HSS ameliorates the diminished hepatocyte regenerative response to partial hepatectomy in this model of acute liver injury, due to Cd intoxication.
Asunto(s)
Cadmio/toxicidad , Sustancias de Crecimiento/farmacología , Hepatectomía , Regeneración Hepática/efectos de los fármacos , Hígado/patología , Mitógenos/farmacología , Péptidos/farmacología , Animales , División Celular/efectos de los fármacos , ADN/biosíntesis , Péptidos y Proteínas de Señalización Intercelular , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Antígeno Nuclear de Célula en Proliferación/análisis , Ratas , Ratas Wistar , Timidina Quinasa/metabolismoRESUMEN
The effect of alpha 2b-interferon administration on liver regeneration after partial hepatectomy in male Wistar rats was examined 24 hours after the operation. Tritium thymidine incorporation into liver DNA, liver mass restitution, mitotic index, and nuclear expression of proliferating cell nuclear antigen were determined as indexes of hepatic proliferation. Both early and late alpha 2b-interferon administration, 2 and 12 hours, respectively, after partial hepatectomy, at a dose of 3.3 x 10(4) IU per kg body weight, suppressed tritium thymidine incorporation and liver mass restitution (p < 0.001) when compared with that in untreated partially hepatectomized rats. The enzyme thymidine kinase (EC 2.7.1.21), a rate-determining enzyme of DNA biosynthesis, has been implicated in the suppression of proliferation in interferon-treated cell cultures. However, in the above-mentioned in vivo model of controlled cellular proliferation, thymidine kinase activity was not affected by alpha 2b-interferon administration, whereas DNA biosynthesis was inhibited. These findings, in contrast to previous observations in in vitro models, show that the inhibition of the in vivo liver regeneration by alpha 2b-interferon is not due to the inhibition of thymidine kinase activity. The expression of the cell cycle-related genes' products c-myc, p53, and c-erbB-2 proteins--which increase during the prereplicative phase that precedes DNA synthesis--was affected by interferon administration, being in accordance with liver proliferative status.
Asunto(s)
Hepatectomía/métodos , Interferón-alfa/farmacología , Regeneración Hepática/efectos de los fármacos , Hígado/enzimología , Timidina Quinasa/metabolismo , Animales , Sangre/metabolismo , División Celular , Interferón alfa-2 , Hígado/patología , Masculino , Ratas , Ratas Wistar , Proteínas RecombinantesRESUMEN
Intraperitoneal administration of a cadmium (Cd) salt at concentrations of 2.5 and 4.0 mg CdCl2/kg of body wt., caused time-dependent severe liver injury, in Quinster rats, more intense at the higher administered dose. Thymidine kinase, the key enzyme of the salvage pathway of DNA biosynthesis, was strongly affected in liver tissue and serum of cadmium-intoxicated rats. Lower thymidine kinase activity was observed both in liver and serum of rats treated with the higher dose of cadmium, in which the maximal liver injury appeared.
Asunto(s)
Cadmio/toxicidad , Cloruros/toxicidad , Hígado/efectos de los fármacos , Timidina Quinasa/metabolismo , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Cadmio/administración & dosificación , Cloruro de Cadmio , Cloruros/administración & dosificación , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Hígado/enzimología , Masculino , Ratas , Timidina Quinasa/sangreRESUMEN
Proliferating cell nuclear antigen (PCNA) is a nuclear protein maximally elevated in the S phase of proliferating and transformed cells and is recognized by the monoclonal antibody PC-10 in paraffin tissue sections. The liver regenerative process after partial hepatectomy in rats was estimated with the in vivo incorporation of [3H]thymidine into liver DNA and the liver thymidine kinase activity. The expression of PCNA in rat liver after partial hepatectomy was performed by immunohistochemical staining with PC-10 in paraffin embedded tissues, at different time intervals up to 240 hr. Proliferating cell nuclear antigen expression, [3H]thymidine incorporation into DNA, and liver thymidine kinase activity exhibited marked oscillations during the liver regenerative process. A close relationship was demonstrated among DNA synthesis, thymidine kinase activity, and PC-10 score. Our results suggest that PC-10 monoclonal antibody may be used as a worthwhile proliferation index in the evaluation of the rate of liver regeneration in rats.
Asunto(s)
Regeneración Hepática/fisiología , Hígado/metabolismo , Proteínas Nucleares/análisis , Animales , División Celular/fisiología , Hepatectomía , Técnicas para Inmunoenzimas , Hígado/citología , Hígado/enzimología , Masculino , Antígeno Nuclear de Célula en Proliferación , Ratas , Ratas Wistar , Timidina Quinasa/metabolismoRESUMEN
Cadmium (Cd) is a highly toxic element able to induce acute liver injury in rats after intraperitoneal administration. The dose-dependent Cd-induced hepatotoxicity was examined in three different rat strains. A difference in hepatotoxicity was observed in the three rat strains, determined by the examination of serum enzymes' activities and other biochemical parameters, all markedly altered after Cd intoxication. The histological findings came to confirm the variations of the above-mentioned parameters. It is concluded that the administration of this toxic agent caused different toxicity in the three rat strains examined, indicating a more intense damage in Wistar than in Quinster and Lewis rats.
Asunto(s)
Cadmio/toxicidad , Hígado/efectos de los fármacos , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Proteínas Sanguíneas/metabolismo , Cadmio/administración & dosificación , Cadmio/farmacocinética , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Hígado/metabolismo , Masculino , Ratas , Ratas Endogámicas Lew , Ratas Wistar , Especificidad de la Especie , Espectrofotometría Atómica , Triglicéridos/sangreRESUMEN
Metallothionein is a low molecular mass protein inducible mainly by heavy metals, having high affinity for binding cadmium, zinc and copper. In the present study we investigated the expression of metallothionein in regenerating liver, at different time intervals, in cadmium pretreated partially hepatectomized rats. Liver metallothionein is highly expressed during regeneration induced by partial hepatectomy in rats, providing zinc within the rapidly growing tissue. Cadmium pretreatment caused inhibition of the first peak of liver regeneration, while metallothionein expression was markedly more prominent in the liver residues of cadmium-pretreated rats. These results demonstrate that although metallothionein able to bind temporarily metal ions as zinc and cadmium has been highly expressed, the liver regenerative process was inhibited possibly due to the effects of cadmium on other pivotal events necessary to the DNA replication.
Asunto(s)
Cadmio/toxicidad , Cloruros/toxicidad , Regeneración Hepática/fisiología , Metalotioneína/biosíntesis , Animales , Cadmio/administración & dosificación , Cadmio/metabolismo , Cloruro de Cadmio , Intoxicación por Cadmio , Cloruros/administración & dosificación , Cloruros/metabolismo , ADN/biosíntesis , Modelos Animales de Enfermedad , Hepatectomía , Inmunohistoquímica , Modelos Lineales , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/fisiología , Masculino , Metalotioneína/metabolismo , Unión Proteica , Ratas , Ratas Wistar , Espectrofotometría Atómica , Timidina Quinasa/metabolismo , Zinc/sangre , Zinc/metabolismoRESUMEN
Intraperitoneal (i.p.) administration of a cadmium (Cd) salt at concentrations of 1.0, 2.5 and 4.0 mg CdCl2/kg body wt. caused severe liver injury in rats 24 h after administration. The toxic effects were most evident in the intermediate dose of 2.5 mg. Thymidine kinase (TK), the key enzyme of the salvage pathway of DNA biosynthesis, was affected in all Cd-treated groups. TK activity presented lower values at the highest Cd-induced hepatotoxicity.