RESUMO
We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.
Assuntos
Etanol/farmacologia , Ferroquelatase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Porfiria Cutânea Tardia/induzido quimicamente , Solventes/farmacologia , Uroporfirinogênio Descarboxilase/efeitos dos fármacos , Animais , Sistema Enzimático do Citocromo P-450/análise , Modelos Animais de Doenças , Feminino , Ferroquelatase/metabolismo , Hexaclorobenzeno , Fígado/enzimologia , Fígado/patologia , Porfobilinogênio/urina , Sintase do Porfobilinogênio/urina , Porfiria Cutânea Tardia/enzimologia , Porfiria Cutânea Tardia/urina , Porfirinas/urina , Ratos , Ratos Wistar , Uroporfirinogênio Descarboxilase/metabolismoRESUMO
We evaluated the porphyrinogenic ability of ethanol (20 percent in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30 percent decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda
Assuntos
Animais , Feminino , Ratos , Etanol , Ferroquelatase , Fígado , Porfiria Cutânea Tardia , Uroporfirinogênio Descarboxilase , /análise , Modelos Animais de Doenças , Ferroquelatase , Hexaclorobenzeno , Fígado , Porfobilinogênio , Sintase do Porfobilinogênio , Porfiria Cutânea Tardia , Porfirinas , Ratos Wistar , Uroporfirinogênio DescarboxilaseRESUMO
The aim of the present study was to determine whether short-term administration of hexachlorobenzene (HCB) (1 g/kg body wt., suspended in water, 5 days/week), could cause and maintain marked porphyria in the absence of the exogenous drug, and whether porphyria parameters can be useful as biomarkers of HCB persistence in rats. Hepatic uroporphyrinogen decarboxylase activity, its inhibitor formation, porphyrin content and composition were studied in Wistar rats treated with the fungicide for 1, 2, 3, or 4 weeks and then withdrawn for a 20-week period. The time course of urinary porphyrin excretion was studied for 7 weeks either by continuous treatment for the entire period, or a 1-week HCB administration. The degree of porphyria achieved by rats after 20 weeks of suspended HCB administration was severe, independent of the length of the treatment, and even higher than that observed in animals analysed immediately at the end of each treatment. Rats treated with HCB for 1 week showed a modest decrease in uroporphyrinogen decarboxylase and low inhibitor formation, and exhibited a greater enzyme inhibition, inhibitor formation, hepatic porphyrin accumulation, and an altered pattern of porphyrin composition in the absence of the exogenous drug. Independent of the treatment, urinary porphyrins rose after a delay of 5 weeks. Substantial amounts of HCB were still found in fat of rats treated with HCB for 1 week, after a withdrawal period of 20 weeks. These results suggest that the high persistence of HCB in tissues acts as a continuous source of the xenobiotic, and stimulus for heme biosynthesis derangement. The alterations induced by HCB within 1 week of treatment could be regarded as an initial trigger for irreversible damage on heme metabolism. Thus, abnormalities in heme biosynthesis can be considered effective markers of HCB persistence in rats or of irreversible HCB-induced damage. Taking into account the delayed and enhanced metabolic effects of HCB, it is advisable that porphyria parameters should be evaluated not only immediately after exposure, but also some time afterwards, especially in susceptible and occupationally-exposed populations.
Assuntos
Fungicidas Industriais/toxicidade , Heme/metabolismo , Hexaclorobenzeno/toxicidade , Porfirias/induzido quimicamente , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Animais não Endogâmicos , Biomarcadores/análise , Esquema de Medicação , Inibidores Enzimáticos/toxicidade , Feminino , Fungicidas Industriais/administração & dosagem , Fungicidas Industriais/farmacocinética , Hexaclorobenzeno/administração & dosagem , Hexaclorobenzeno/farmacocinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Porfirias/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo , Uroporfirinogênio Descarboxilase/antagonistas & inibidores , Uroporfirinogênio Descarboxilase/metabolismoRESUMO
In the present study, the effects of hexachlorobenzene (HCB) on lipid peroxidation and heme metabolism in the different constitutive suborgans of the kidney were determined. For this purpose, conjugated diene and malondialdehyde levels, as lipid peroxidation parameters, and porphyrin accumulation, uroporphyrinogen decarboxylase activity, and its inhibitor formation, as measures of heme metabolism, were determined in renal cortex, medulla, and papilla. Adult Wistar rats were treated with HCB during 1, 2, 3, or 4 weeks. A significant increase in cortical conjugated dienes was observed from the 1st week of treatment. The malondialdehyde levels rose by 47, 34, and 28% after 2, 3, and 4 weeks of intoxication, respectively. The porphyrin content showed a tenfold increase after 4 weeks of treatment, and the uroporphyrinogen decarboxylase activity was reduced by 26 and 58% with respect to control values after 3 and 4 weeks of treatment, respectively. The results demonstrate a direct correlation between the oxidative environment and the effect elicited by the drug on heme metabolism in the renal cortex. In contrast, in papilla and medulla, where the antioxidant systems were higher, HCB showed no porphyrinogenic effect.
Assuntos
Heme/metabolismo , Hexaclorobenzeno/toxicidade , Rim/citologia , Peroxidação de Lipídeos/efeitos dos fármacos , Porfirias/metabolismo , Animais , Biomarcadores , Inibidores Enzimáticos/farmacologia , Feminino , Rim/efeitos dos fármacos , Córtex Renal/metabolismo , Fígado/metabolismo , Malondialdeído/metabolismo , Porfirias/induzido quimicamente , Porfirinas/metabolismo , Ratos , Ratos Wistar , Uroporfirinogênio Descarboxilase/antagonistas & inibidores , Uroporfirinogênio Descarboxilase/metabolismoRESUMO
Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with substrate decarboxylation sites on the enzyme, was studied using four different carboxylated substrates belonging to the isomeric III series of naturally-formed porphyrinogens containing 8-,7-,6- and 5-COOH. Similar inhibitor effects were elicited against all the substrates assayed, with the exception of pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same extent. Enzyme protection assays in the presence of the different substrates, indicated that each porphyrinogen protects its own decarboxylation from inhibitor action. Preincubation of the inhibitor with normal enzyme increased its inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor with superoxide dismutase or mannitol, did not alter inhibitory activity. Preincubation of the inhibitor with a number of amino acids showed that only arginine and its derivative N alpha-Benzoyl-L-Arginine ethyl ester interact with the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy-lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench inhibitor activity. The present results indicate that the inhibitor acts at the binding site of each porphyrinogen. Taking into account that arginine is related to enzyme activity, and that histidine is found at the binding site of the substrates, the results suggest that the inhibitor could bind to arginine residues, blocking the access of substrates to histidine and altering the adequate orientation for decarboxylation by masking the positively charged active site necessary for porphyrinogen binding to the enzyme. In addition an indirect effect of the inhibitor mediated through free radicals could be discarded.
Assuntos
Carboxiliases/antagonistas & inibidores , Porfirinogênios/metabolismo , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Feminino , Hexaclorobenzeno/farmacologia , Humanos , Fígado/enzimologia , Porfirias/induzido quimicamente , Ratos , Ratos Wistar , Uroporfirinogênios/metabolismoRESUMO
The aim of this work is to study the effect of thioctamide--the commercial form of alpha lipoic acid amide--on the porphyrinogenic action of hexachlorobenzene (HCB). For this purpose, porphyria was induced in rats by chronic HCB treatment, with or without simultaneous thioctamide administration. Two different groups of rats were used as reference: one treated with vehicle (control) and the other treated with thioctamide (TO). Urine delta aminolevulic acid, porphobilinogen, and porphyrin excretions were lower in the HCB + TO treated group than in the HCB group, and the same happened with liver uroporphyrin accumulation. On the other hand, the second stage of uroporphyrinogen-decarboxylase activity was significantly higher in the HCB + TO group than in the HCB group. delta aminolevulic acid synthase activity was higher in the HCB group. Hepatic thiobarbituric acid reactive substances were lower in HCB + TO group than in HCB group. Thus, we might suggest that TO would decrease HCB effects by means of its free radical scavenging ability, and by having a direct effect on uroporphyrinogen-decarboxylase activity.
Assuntos
Hexaclorobenzeno/metabolismo , Porfirias/induzido quimicamente , Porfirias/tratamento farmacológico , Ácido Tióctico/farmacologia , Animais , Feminino , Sequestradores de Radicais Livres/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Chronic administration of Hexachlorobenzene, with or without the simultaneous administration of Tioctamide was assayed. Hexachlorobenzene alone produced the characteristic porphyria, detected through an increase of the urinary excretion and the hepatic accumulation of porphyrins, as well as by a decrease of the Uroporphyrinogen decarboxylase activity. The content of hepatic conjugated dienes did not change while those of malondialdehyde increased, although without reaching levels of statistical significance. These results would indicate the occurrence of an light lipid peroxidation process. The Thioctamide (25 mg/kg body weight) produced more noxious effects than protective ones, which were detected by a high level of Glutamate piruvate transaminase activity and a decrease of the hepatic Uroporphyrinogen decarboxylase activity, at its first step of decarboxylation. These results might indicate that: 1) high doses of Thioctamide decreases Uroporphyrinogen decarboxylase activity, masking its possible protective effect from Hexachlorobenzene's action through free radicals production and, 2) Uroporphyrinogen decarboxylase is a more sensitive parameter than conjugated dienes or malondialdehyde levels to assay the free radicals in vivo Hexachlorobenzene production. In any case, the Thioctamide assayed in lower and non toxic doses, perhaps might protect against Hexachlorobenzene's action through its free radical scavenger ability.
Assuntos
5-Aminolevulinato Sintetase/urina , Alanina Transaminase/efeitos dos fármacos , Amidas/farmacologia , Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/química , Porfobilinogênio/urina , Porfirinas/urina , Ácido Tióctico/farmacologia , Uroporfirinogênio Descarboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Radicais Livres/metabolismo , Fígado/enzimologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Se estudió el efecto de la intoxicación crónica con hexaclorobenceno en ratas, con y sin administración simultánea de tioctamida. En el grupo que recibió hexaclorobenceno solo, se produjo el esperado desarrollo de porfiria incrementándose la excreción urinaria y el contenido hepático de porfirinas y disminuyendo la actividad Uroporfirinógeno decarboxilasa. El contenido hepático de dienos conjugados no varió, en tanto que el de malondialdehido se incrementó en un grado estadísticamente no significativo. Estos resultados indicarían la existencia de un ligero proceso de peroxidación lipídica. La tioctamida (25 mg/Kg de peso) produjo efectos nocivos antes que protectores, detectados por un aumento de la actividad transaminasa glutámico pirúvica y una inhibición a nivel de la primera etapa de la Uroporfirinógeno decarboxilasa. Los resultados indicarían que: 1) altas dosis de tioctamida producen un decremento en la actividad Uroporfirinógeno decarboxilasa, enmascarando quizás su posible efecto protector frente a la acción del hexaclorobenceno por radicales libres; 2) la Uroporfirinógeno decarboxilasa es un parámetro más sensible que la medición de dienos conjugados o de melondialdehido para ensayar la producción de radicales libres por acción del hexaclorobenceno in vivo. De ser así, la tioctamida, ensayada a dosis menores y no tóxicas, a través de su habilidad como atrapante de radicales libres, quizás pueda proteger contra la acción del hexaclorobenceno.
Assuntos
Ratos , Animais , 5-Aminolevulinato Sintetase/urina , Alanina Transaminase/efeitos dos fármacos , Amidas/farmacologia , Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/química , Porfobilinogênio/urina , Porfirinas/urina , Ácido Tióctico/farmacologia , Uroporfirinogênio Descarboxilase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Radicais Livres/metabolismo , Fígado/enzimologia , Ratos Wistar , Fatores de Tempo , Uroporfirinogênio Descarboxilase/efeitos dos fármacosRESUMO
The use of antineoplastics is common in cancer therapy, and some of them have been associated with the development of porphyria in patients with cancer. However, knowledge of their effects on the haeme metabolic pathway is at present scarce and unclear. So, the present study evaluates the porphyrinogenic ability of nine antineoplastics (both alkylating and non-alkylating). These were tested either alone or in conjunction with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (latent porphyria model) in chick embryos and in mice. The results obtained suggest that the use of cyclophosphamide, azathioprine, 5-fluorouracil, busulphan, procarbazine and hexamethylmelamine be avoided in the treatment of porphyric patients. On the other hand, dacarbazine, chlorambucil and melphalan are non-porphyrinogenic. We also provide evidence showing that neither the presence of the mustard group in the structure of the antineoplastic nor alterations in ferrochelatase or protoporphyrinogen oxidase activities are responsible for the porphyrinogenic ability of cyclophosphamide.
Assuntos
Antineoplásicos/toxicidade , Dicarbetoxi-Di-Hidrocolidina/toxicidade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Porfirias/induzido quimicamente , Alquilantes/toxicidade , Altretamine/toxicidade , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Azatioprina/toxicidade , Bussulfano/toxicidade , Embrião de Galinha , Ciclofosfamida/efeitos adversos , Ciclofosfamida/química , Ciclofosfamida/toxicidade , Dacarbazina/toxicidade , Feminino , Ferroquelatase/efeitos dos fármacos , Ferroquelatase/metabolismo , Flavoproteínas , Fluoruracila/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Mitocondriais , Oxirredutases/efeitos dos fármacos , Oxirredutases/metabolismo , Porfirinas/metabolismo , Procarbazina/toxicidade , Protoporfirinogênio Oxidase , Relação Estrutura-AtividadeRESUMO
A great deal of information concerning the effects of hexachlorobenzene on the haem metabolic pathway has been obtained but little is known about the effects of the drug on lipid metabolism. Consequently, the time course of phospholipid metabolism alteration caused by this xenobiotic was evaluated as related to changes in porphyrin metabolism with the aim to understand better the interregulation of both metabolisms. Female Wistar rats were treated with HCB (1 g/kg) over a 1-8 week period. Individual phospholipid content, [32P] incorporation, total lipid content, lipid peroxidation, uroporphyrinogen decarboxylase activity, its inhibitor generation and porphyrin content, were the parameters measured in the liver of treated rats. Phospholipid metabolism-with the exception of sphingomyelin-presents a biphasic behaviour, in both the endogenous contents and de novo synthesis. The turning point between both phases is the time at which levels of porphyrin and conjugated dienes increase, the latter compounds being involved in oxidative processes. On the other hand, sphingomyelin decreases continuously during the 8 weeks of treatment. It was also found that the malondialdehyde content increased during the early stages. The time sequence for haem metabolism parameters showed that the accumulation of porphyrins occurs after the decrease in uroporphyrinogen decarboxylase activity and the enzyme inhibitor formation, which are early events (first and second weeks). Porphyrins could not by themselves exacerbate uroporphyrinogen decarboxylase impairment or inhibitor generation. This study shows that hexachlorobenzene alters simultaneously phospholipid and porphyrin metabolisms from the early stages, and generates an oxidative environment that favours porphyrinogens and lipid oxidation at later stages. So, this oxidative environment links the alterations on both metabolisms.
Assuntos
Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Metabolismo dos Lipídeos , Porfirias/induzido quimicamente , Animais , Feminino , Peroxidação de Lipídeos , Porfirias/metabolismo , Ratos , Ratos WistarRESUMO
Uroporphyrinogen I Synthase (URO-S) activity was measured in erythrocytes of female and male rats which had received diethylnitrosamine (DENA) as an inducer of hepatic tumors. Twenty-two weeks after the last dose of the carcinogen, the rats showed statistically significant increases in the URO-S activity. Differences in the body weight, erythrocyte porphyrin content or the hematocrit between treated and control rats were not found. Fifty percent of female rats and thirty percent of male rats treated with DENA were found to have hepatic tumors but there was no correlation between blood URO-S activity and tumoral development in spite of the increase in URO-S activity observed in DENA treated rats. This was observed both in male and female rats.
Assuntos
Carcinoma Hepatocelular/enzimologia , Dietilnitrosamina/uso terapêutico , Eritrócitos/metabolismo , Hidroximetilbilano Sintase/metabolismo , Neoplasias Hepáticas/enzimologia , Animais , Feminino , Hidroximetilbilano Sintase/sangue , Masculino , RatosRESUMO
Se midió la actividad de Uroporfirinógeno I sintasa (URO-S) en eritrocitos de ratas hembras y machos que habían recibido dietilnitrosamina (DENA) como inductor de tumores hepáticos. Veintidós semanas después de la última dosis del carcinógeno, las ratas mostraron incrementos estadísticamente, significativos en la actividad de URO-S. No se encontraron diferencias en el peso de los animales, en el contenido de porfirinas eritrocitarias ni en el hematocrito entre las ratas tratadas y los animales control. Se observó que el cincuenta por ciento de las ratas hembras y el treinta por ciento de las ratas machos tratadas con DENA habían desarrollado tumores hepáticos pero no hubo correlación, ni en machos ni en hembras, entre la actividad de URO-S y el desarrollo tumoral a pesar del incremento obtenido en los animales tratados con DENA en la actividad de esta enzima
Assuntos
Animais , Masculino , Feminino , Ratos , Carcinoma Hepatocelular/induzido quimicamente , Dietilnitrosamina/uso terapêutico , Hidroximetilbilano Sintase/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Hidroximetilbilano Sintase/sangueRESUMO
The present study was undertaken to explore the effect of the presence of hepatic tumors induced by diethylinitrosamine (DENA) on the metabolic heme pathway, and to assess whether these tumors can modify the response of rats to the porphyrinogenic drug hexachlorobenzene (HCB) and whether the above mentioned effects occur to a greater extent in females than males. The results obtained showed that: a) Females were more susceptible to the hepatocarcinogenicity of DENA than males. b) Female normal and DENA treated rats were more susceptible than male rats to the porphyrinogenicity of HCB. c) The presence of hepatic DENA induced tumors could diminish basal hepatic ferrochelatase activity. d) Hepatic tumors could modify the response of animals to a porphyrinogenic drug such as HCB. Thus, both female and male DENA/HBC rats accumulated more porphyrins and showed a lower delta-aminolevulinate synthase and uroporphyrinogen I synthase induction than HCB rats. e) The heme pathway was functional in DENA induced tumors in both male and female rats but they were little affected by HCB.
Assuntos
Heme/metabolismo , Neoplasias Hepáticas Experimentais/enzimologia , Porfirias/enzimologia , Porfirinas/metabolismo , Caracteres Sexuais , 5-Aminolevulinato Sintetase/metabolismo , Animais , Carboxiliases , Sistema Enzimático do Citocromo P-450/metabolismo , Dietilnitrosamina , Feminino , Ferroquelatase/metabolismo , Hexaclorobenzeno , Hidroximetilbilano Sintase/metabolismo , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Porfirias/induzido quimicamente , RatosRESUMO
The response of female BDVI rats bearing diethylnitrosamine(DENA)-induced hepatic tumors to the porphyrinogenic action of hexachlorobenzene (HCB) was studied. (1) The heme pathway operates in these tumors but they were less affected by HCB than the liver. (2) Tumors did not accumulate porphyrins although the surrounding liver accumulated more porphyrins than livers treated with HCB. (3) DENA/HCB livers which developed a well defined tumor showed slightly less porphyrinogen carboxylyase inhibition and delta-aminolaevulinate synthase induction than HCB rats. (4) The results of the present work suggest that endogenously formed porphyrins would be unable to be accumulated by DENA-induced tumors when the tumoral development precedes the onset of the porphyria.
Assuntos
Carcinoma Hepatocelular/complicações , Dietilnitrosamina/farmacologia , Hexaclorobenzeno/farmacologia , Neoplasias Hepáticas/complicações , Porfirias/metabolismo , 5-Aminolevulinato Sintetase/metabolismo , Ácido Aminolevulínico/urina , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Ferroquelatase/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Porfobilinogênio/urina , Porfirias/etiologia , Porfirinas/metabolismo , RatosRESUMO
The response of animals bearing N-nitroso-N-methylurea (NMU)-induced mammary tumors to the porphyrinogenic action of hexachlorobenzene (HCB) was studied. delta-Aminolevulinic acid (ALA), porphobilinogen and porphyrins in urine, ALA-synthase and porphyrinogen carboxylase activities and porphyrin content in liver and tumor were measured. The results obtained indicate that the metabolic heme pathway operates in mammary tumors but tumor response to HCB treatment could not be detected. HCB administration produced an earlier and greater hepatic porphyria in tumor-bearing rats than in healthy rats suggesting that the presence of tumors exacerbates the action of HCB.
Assuntos
Hexaclorobenzeno/toxicidade , Neoplasias Mamárias Experimentais/complicações , Porfirias/induzido quimicamente , 5-Aminolevulinato Sintetase/metabolismo , Animais , Feminino , Neoplasias Mamárias Experimentais/metabolismo , Porfirias/metabolismo , Porfirinas/metabolismo , Ratos , Ratos EndogâmicosRESUMO
1. The present work undertakes a comparative study on the hexachlorobenzene (HCB) porphyria induction in female rats of Wistar and CHBBTHOM strains. The purpose was to characterize the CHBBTHOM strain with respect to the haem metabolic pathway, its regulatory mechanisms and its response to foreign drugs. 2. After 7 weeks of treatment it was observed that the hepatic porphyrins increased 140 times, ALA-synthase 4 times and PCL was 73% inhibited in the Wistar strain. 3. On the other hand the animals of CHBBTHOM strain showed lesser alteration on these parameters; hepatic porphyrins increased only 3-fold, ALA-synthase 1.7-fold and PLC was only 22% inhibited. 4. Total iron liver content was nearly equal in both strains of rats. 5. The results obtained would indicate that the lower susceptibility of the CHBBTHOM strain to acquire porphyria does not seem to be due to either: (1) congenital alterations of any parameters of the haem metabolic pathway, since the behaviour of normal animals from both strains was similar; or (2) a lower hepatic iron content in such animals. 6. These findings would suggest that the differential response to HCB to this strain would be looked for in another metabolic pathway, such as that involved in the metabolization process of the toxic.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Clorobenzenos/toxicidade , Hexaclorobenzeno/toxicidade , Porfirias/induzido quimicamente , 5-Aminolevulinato Sintetase/metabolismo , Animais , Carboxiliases/metabolismo , Feminino , Ferro/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Porfirias/metabolismo , Porfirinas/metabolismo , Porfirinas/urina , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
The purpose of the present work is to investigate the ability of desferrioxamine (DF) as an iron chelator to revert or decrease a severe experimental porphyria induced by hexachlorobenzene (HCB) in rats; DF treatment started after 17 weeks of HCB intoxication and was continued until the 27th week. The urinary excretions of -aminolevulinic acid (ALA), porphobilinogen and porphyrins were weekly quantitated. At the end of the experiment the animals were sacrificed and hepatic porphyrins, ALA-synthase and porphyrinogen carboxy-lyase activities were determined. The results obtained indicated that, under the present conditions, the administered iron chelator does not improve the disturbance promoted by HCB on the haem pathway. These results were compared with those obtained when the DF was given simultaneously with HCB from the beginning of fungicide administration. In this last situation the chelator was able to delay and diminish the porphyrinogenic effect of HCB.
Assuntos
Desferroxamina/uso terapêutico , Porfirias/tratamento farmacológico , Dermatopatias/tratamento farmacológico , 5-Aminolevulinato Sintetase/metabolismo , 5-Aminolevulinato Sintetase/urina , Animais , Carboxiliases/metabolismo , Hexaclorobenzeno , Fígado/enzimologia , Porfobilinogênio/urina , Porfirias/induzido quimicamente , Porfirias/enzimologia , Porfirias/urina , Porfirinas/metabolismo , Porfirinas/urina , Ratos , Ratos Endogâmicos , Indução de Remissão , Dermatopatias/induzido quimicamente , Dermatopatias/enzimologia , Dermatopatias/urinaRESUMO
The present work deals with the effect of desferrioxamine (DF) on hexachlorobenzene (HCB)-induced porphyria in female rats with the purpose of further investigation of the role of iron in the development of this porphyria. The results obtained show that the repeated injection of DF (three times a week: 100 mg/kg each i.m.) delayed and diminished remarkably the urinary excretion of precursors and porphyrins as well as the accumulation of the latter in liver promoted by HCB (1 g/kg daily given by stomach tube). This was probably due to attenuation by DF of the alterations produced by the fungicide in the two key enzymes: porphyrinogen carboxy-lyase (PCL) and delta-aminolaevulinate synthase (ALA-S). In fact, DF by reducing liver iron levels produced a smaller decrease of the target enzyme (PCL) and a concomitant smaller induction of ALA-S. DF alone did not modify any of these variables or the liver to body weight ratio. DF added at 10(-2) and 10(-3) M to the incubation media of ALA-S and PCL did not alter either of the enzymatic activities, whether in normal or HCB-porphyric preparations. The results obtained show that DF improved the biochemical picture during HCB porphyria. They suggest that iron plays an indirect role in the decrease of PCL enzyme, possibly at the HCB metabolization step. A common iron-involving mechanism for the production of porphyria by different chlorinated compounds is suggested.
Assuntos
Clorobenzenos/toxicidade , Desferroxamina/uso terapêutico , Hexaclorobenzeno/toxicidade , Porfirias/induzido quimicamente , 5-Aminolevulinato Sintetase/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Carboxiliases/antagonistas & inibidores , Desferroxamina/farmacologia , Modelos Animais de Doenças/metabolismo , Feminino , Hexaclorobenzeno/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Porfirias/metabolismo , Porfirias/prevenção & controle , Porfirinas/metabolismo , Ratos , Dermatopatias/metabolismoRESUMO
In order to study the porphyrinogenic ability of lindane in mammals, rats were treated with the pesticide suspended with the aid of Tween or dissolved in oil during about 3 months. The urinary excretion of porphyrins and its precursors: delta-aminolaevulinate (ALA) and porphobilinogen (PBG), as well as the faecal excretion of coproporphyrin (COPRO) and protoporphyrin (PROTO) was determined weekly. At the end of the treatment the hepatic activities of ALA Synthase (ALA-S), the first and rate limiting enzyme of haem pathway, and porphyrinogen carboxy-lyase (PCL), enzyme which sequentially decarboxylates uroporphyrinogen (8 COOH) to coproporphyrinogen (4 COOH), were assayed. Lindane moderately increased the urinary excretion of porphyrins and its precursors, being the former the mainly affected parameter. The faecal excretion of COPRO and PROTO was also increased. However, the hepatic activity of ALA-S was not altered. This would suggest that the regulatory haem pool was not affected. Nor was PCL activity altered in spite of being the key enzyme for the attack of other chlorinated compounds. Although hexachlorobenzene (HCB), a very well known porphyrinogenic drug, and lindane are chemically related and generate similar metabolites, the last one produces a small and qualitatively different alteration of haem biosynthesis. This may be related with the absence or scarce formation of the reactive metabolite that accounts for the porphyrinogenic ability of HCB.
Assuntos
Ácido Aminolevulínico/urina , Hexaclorocicloexano/farmacologia , Ácidos Levulínicos/urina , Porfobilinogênio/urina , Porfirinas/metabolismo , 5-Aminolevulinato Sintetase/metabolismo , Animais , Heme/metabolismo , Fígado/metabolismo , Masculino , Porfirias/metabolismo , Porfirinas/urina , Ratos , Ratos EndogâmicosRESUMO
The effect of desferrioxamine on hexachlorobenzene (HCB)-induced porphyria was studied in female rats in order to investigate the role of iron in the development of this porphyria. Repeated injections of desferrioxamine delayed and remarkably diminished the urinary excretion of precursors and porphyrins and the accumulation of porphyrins in the liver. These effects were produced because the desferrioxamine attenuated the alterations produced by HCB in two key enzymes: porphyrinogen carboxy-lyase and delta-aminolaevulinic acid synthase. The effect of desferrioxamine on both enzymes was also studied in vitro. This work showed that iron plays an important role in the onset of HCB-induced porphyria and supplied information on the mechanism of action. A common iron-involving mechanism for the production of porphyria by different chlorinated compounds is suggested.