RESUMO
Porphyrias neuropathophysiology could be related to low levels of heme as a cofactor for nitric oxide synthase (NOS). We examined how anaesthetics and other porphyrinogenic agents affect mice NOS activity and expression. Brain response was differential depending on the cellular fraction analyzed. Most of the drugs diminished cytosolic activity. Instead, isoflurane, enflurane and ethanol increased mitochondrial activity. NOS expression also depended on the drug tested. A comparative study was performed in liver. Our present and previous results indicate the widespread action of porphyrinogenic agents in brain, which could be the reason why it is difficult to establish the onset of acute porphyria neurological manifestations.
Assuntos
Anestésicos/farmacologia , Encéfalo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Óxido Nítrico Sintase/biossíntese , Porfirias/enzimologia , Anestésicos/toxicidade , Animais , Encéfalo/enzimologia , Fracionamento Celular , Citosol/efeitos dos fármacos , Citosol/enzimologia , Indução Enzimática , Fígado/enzimologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Porfirias/induzido quimicamenteRESUMO
This study focuses on the alterations suffered by the serotoninergic and kinurenergic routes of tryptophan (TRP) metabolism in liver, and their relation with gluconeogenic phosphoenolpyruvate-carboxykinase (PEPCK) blockage in experimental acute porphyria. This porphyria was induced in rats by a combined treatment of 2-allyl-2-isopropylacetamide (100, 250, 500 mg/kg bw) and 3,5-dietoxicarbonil 1,4-dihydrocollidine (constant 50 mg/kg bw dose). Results showed a marked dose-dependent increase of all TRP pyrrolase (TRPp) forms, active (holo, total) and inactive (apo), and a decrease in the degree of enzyme saturation by heme. Increases for holo, total, and apo-TRPp were 90, 150, and 230%, respectively, at the highest dose assayed (H). The treatment also impaired the serotoninergic route of TRP metabolism in liver, causing a decrease in serotonin level (H, 38%), and a concomitant enhancement in TRP content (H, 23%). The porphyrinogenic treatment promoted a blockage in PEPCK activity (H, 30%). This occurred in correlation to the development of porphyria, to TRPp alterations and to the production of hepatic microsomal thiobarbituric acid reactive substances. Porphyria was estimated through increases in 5-aminolevulinic acid-synthase (ALA-S) activity, ALA and porphobilinogen contents, and a decrease in ferrochelatase activity. Thus, the TRP kynurenine route was augmented whereas the serotoninergic route was reduced. PEPCK blockage could be partly attributed to quinolinate generated from TRP by the increase of TRPp activity, which would be due to the effect of porphyrinogenic drugs on TRP. The contribution of ROS to PEPCK blockage is analyzed. Likewise, the implication of these results in the control of porphyrias by glucose is discussed.
Assuntos
Gluconeogênese , Fígado/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/antagonistas & inibidores , Porfirias/metabolismo , Triptofano/metabolismo , 5-Aminolevulinato Sintetase/metabolismo , Doença Aguda , Alilisopropilacetamida/toxicidade , Animais , Dicarbetoxi-Di-Hidrocolidina/toxicidade , Relação Dose-Resposta a Droga , Feminino , Porfirias/induzido quimicamente , Ratos , Ratos WistarRESUMO
Menopause is defined as the permanent cessation of menses, as a result of the loss of ovarian follicular function or of surgical removal of ovaries. The mean age for occurrence of natural menopause is around 50 years. Estrogen deficiency has been associated with vasomotor symptoms, urogenital atrophy, and cognitive impairment, as well as increased risk of chronic degenerative diseases such as osteoporosis and Alzheimer's disease. Estrogen therapy remains the most effective treatment for the management of vasomotor symptoms and urogenital atrophy. Progesterone or progestins should be added to estrogen treatment in women with uterus, in order to antagonize the estrogen-induced endometrial proliferation. In turn, in specific clinical conditions hormone therapy is not recommended. In the present article, the authors critically focus these clinical conditions in which hormone therapy should not be used.
Assuntos
Terapia de Reposição Hormonal , Menopausa/efeitos dos fármacos , Neoplasias da Mama/induzido quimicamente , Carcinoma/induzido quimicamente , Contraindicações , Neoplasias do Endométrio/induzido quimicamente , Terapia de Reposição de Estrogênios , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Porfirias/induzido quimicamente , Fatores de Risco , Tromboembolia/induzido quimicamenteRESUMO
A menopausa corresponde à cessação permanente da menstruação, conseqüente à perda da função folicular ovariana ou à remoção cirúrgica dos ovários. A idade média para ocorrência da menopausa natural gira em torno de 50 anos. A deficiência estrogênica decorrente da menopausa está associada com sintomas vasomotores, atrofia urogenital, declínio cognitivo, assim como a um aumento no risco de doenças crônico-degenerativas, aterosclerose e doença cardiovascular, osteoporose e doença de Alzheimer. A estrogenioterapia permanece sendo o tratamento mais efetivo para o manejo dos sintomas vasomotores e atrofia urogenital. Em mulheres com útero presente, a progesterona natural ou os progestogênios devem ser associados ao tratamento com estradiol para antagonizar os efeitos proliferativos deste hormônio sobre o endométrio e anular o risco de hiperplasia/carcinoma endometrial. Por outro lado, em determinadas condições clínicas, a terapia hormonal não é recomendada ou é mesmo contra-indicada. Neste artigo, focalizamos criticamente essas situações clínicas em que não se deve indicar a terapia hormonal na menopausa.
Menopause is defined as the permanent cessation of menses, as a result of the loss of ovarian follicular function or of surgical removal of ovaries. The mean age for occurrence of natural menopause is around 50 years. Estrogen deficiency has been associated with vasomotor symptoms, urogenital atrophy, and cognitive impairment, as well as increased risk of chronic degenerative diseases such as osteoporosis and Alzheimers disease. Estrogen therapy remains the most effective treatment for the management of vasomotor symptoms and urogenital atrophy. Progesterone or progestins should be added to estrogen treatment in women with uterus, in order to antagonize the estrogen-induced endometrial proliferation. In turn, in specific clinical conditions hormone therapy is not recommended. In the present article, the authors critically focus these clinical conditions in which hormone therapy should not be used.
Assuntos
Feminino , Humanos , Terapia de Reposição Hormonal , Menopausa/efeitos dos fármacos , Neoplasias da Mama/induzido quimicamente , Carcinoma/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Terapia de Reposição de Estrogênios , Lúpus Eritematoso Sistêmico/complicações , Porfirias/induzido quimicamente , Fatores de Risco , Tromboembolia/induzido quimicamenteRESUMO
Uroporphyrinogen decarboxylase is an essential enzyme in all organisms and functions in the heme biosynthetic pathway, catalyzing the decarboxylation of the four acetate groups of uroporphyrinogen to form coproporphyrinogen. This work examines whether the four sequential decarboxylations occur at the same active site, and explores whether hexachlorobenzene-induced porphyria affects the behavior of the enzyme. For this purpose, kinetic competition studies were done with mixtures of uroporphyrinogen III and pentacarboxyporphyrinogen III. With the enzyme from normal rats, a constant velocity was obtained with all the mixtures, indicating that uroporphyrinogen and pentacarboxy-porphyrinogen react at the same active site, i.e. the first and fourth decarboxylations occur at the same site. In contrast, in experiments with enzyme from rats with hexachlorobenzene-induced porphyria, the total rate for mixtures was always lower than the reference rate; and a curve with a deep minimum was obtained, indicating that the two reactions occur at functionally different sites, but with cross-inhibition. This suggests that the modifications induced in the enzyme by hexachlorobenzene cause the two active sites to become nonequivalent and functionally different. The question is discussed how the hexachlorobenzene treatment may produce this abnormal kinetic behavior, and alternative hypotheses are considered.
Assuntos
Hexaclorobenzeno/farmacologia , Porfirias/induzido quimicamente , Porfirias/enzimologia , Uroporfirinogênio Descarboxilase/metabolismo , Animais , Feminino , Hexaclorobenzeno/toxicidade , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Porfirinogênios/metabolismo , Ratos , Ratos Wistar , Uroporfirinogênios/metabolismoRESUMO
Hexachlorobenzene (HCB) is a fungicide of well-known porphyrinogenic ability, which induces an experimental porphyria that resembles human porphyria cutanea tarda (PCT) in several animal species. It has been demonstrated that high glucose ingestion prevents porphyria development, and high-fat/high-protein diets enhance HCB porphyrinogenic ability. On the contrary, a diet rich in carbohydrates reduces HCB effects. The aim of this work was to study HCB effects on glycogen synthesis and degradation, as well as on glucose synthesis and transport, in order to elucidate whether would justify the beneficial use of carbohydrates in this porphyria. Rats were treated with HCB dissolved in corn oil (five daily doses 100mg/kg body weight). Results showed that: (1) HCB caused an increase in glycogen content; (2) glycogen synthase activity increased three times, and phosphorylase activity decreased about 40% due to fungicide intoxication. The effect of HCB on these two activities accounted for the higher glycogen content observed in treated animals; (3) three gluconeogenic enzymes were reduced 30-50%; (4) glucose uptake in the liver decreased in all weeks studied. The alterations found in glucose synthesis, its uptake in liver and other tissues, and its release from glycogen might contribute to the biochemical porphyria picture and would account for the effect of glucose above mentioned.
Assuntos
Fungicidas Industriais/toxicidade , Glucose/metabolismo , Glicogênio/metabolismo , Hexaclorobenzeno/toxicidade , Fígado/efeitos dos fármacos , Porfirias/induzido quimicamente , Animais , Modelos Animais de Doenças , Feminino , Gluconeogênese/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Porfirias/enzimologia , Porfirias/metabolismo , Porfirinas/metabolismo , Ratos , Ratos WistarRESUMO
In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.
Assuntos
Encéfalo/metabolismo , Colinesterases/efeitos dos fármacos , Porfirias/complicações , 5-Aminolevulinato Sintetase/efeitos dos fármacos , Acetilcolinesterase/análise , Acetilcolinesterase/efeitos dos fármacos , Animais , Barbital/administração & dosagem , Barbital/farmacologia , Encéfalo/anatomia & histologia , Butirilcolinesterase/análise , Butirilcolinesterase/efeitos dos fármacos , Colinesterases/análise , Enflurano/administração & dosagem , Enflurano/farmacologia , Etanol/administração & dosagem , Etanol/farmacologia , Griseofulvina/administração & dosagem , Griseofulvina/farmacologia , Masculino , Camundongos , Doenças do Sistema Nervoso/etiologia , Porfirias/induzido quimicamente , Receptores Muscarínicos/análise , Receptores Muscarínicos/efeitos dos fármacos , Inanição/metabolismoRESUMO
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
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
The association between an in vivo oxidative stress condition of the liver and hepatic porphyria during HCB intoxication is postulated. After 30 days of treatment, HCB (25 mg/kg b.w.) promotes an induction of microsomal cytochrome P450 system, increase in microsomal superoxide anion generation accompanied by increased levels of liver lipid peroxidation, as measured by the production of thiobarbituric acid reactants and by spontaneous visible chemiluminescence. Concomitantly, liver antioxidant defenses are slightly modified, with decreased activity of glutathione peroxidase, superoxide dismutase and glucose-6-phosphate dehydrogenase contributing to an oxidative stress condition of the liver. These liver biochemical alterations are closely related to increased levels of urinary coproporphyrin, plasma AST and ALT activities and to the onset of liver morphological lesions.
Assuntos
Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Fígado/efeitos dos fármacos , Animais , Coproporfirinas/urina , Sistema Enzimático do Citocromo P-450/metabolismo , Eritrócitos/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Fígado/metabolismo , Masculino , Estresse Oxidativo , Porfirias/induzido quimicamente , Porfirias/metabolismo , Ratos , Ratos WistarRESUMO
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
In the present work, we demonstrate the presence of a glucose inhibitory effect on the phenobarbital-mediated induction of the delta-aminolevulinate synthase mRNA in normal rat hepatocytes, consistent with the results obtained with the delta-aminolevulinate synthase activity previously reported. This "glucose effect" can be prevented by adding cAMP, adenylate cyclase activators, or a phosphodiesterase inhibitor. Delta-Aminolevulinate synthase mRNA half-life is not modified in the presence of phenobarbital or glucose. When the same experiments are performed using diabetic cells, no glucose effect is observed, even when the endogenous cAMP content is lowered to normal levels. The results obtained in this study suggest that glucose decreases delta-aminolevulinate synthase biosynthesis by acting at a pretranslational step. Assuming that the glucose effect operates by a repression mechanism exerted by metabolites derived from or related to glucose, the present results may reflect a derangement in the formation of these metabolites as a result of the abnormal metabolism operating in the diabetic state.
Assuntos
5-Aminolevulinato Sintetase/biossíntese , Diabetes Mellitus Experimental/enzimologia , Glucose/farmacologia , Fígado/efeitos dos fármacos , Fenobarbital/toxicidade , Porfirias/induzido quimicamente , 1-Metil-3-Isobutilxantina/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 5-Aminolevulinato Sintetase/genética , Adenilil Ciclases/metabolismo , Animais , Glicemia/fisiologia , Bucladesina/farmacologia , AMP Cíclico/farmacologia , Diabetes Mellitus Experimental/sangue , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme/biossíntese , Imunidade Inata , Fígado/enzimologia , Masculino , Fenobarbital/antagonistas & inibidores , Fenobarbital/farmacologia , Porfirias/etiologia , Ratos , Sistemas do Segundo Mensageiro/fisiologia , EstreptozocinaRESUMO
Children with rheumatic disease (N = 250) were examined for shallow facial scars similar to those described in drug-induced pseudoporphyria. Users of a nonsteroidal antiinflammatory drug were 2.4 times as likely as nonusers to have four or more facial scars; this relative risk was increased to 6.0 in users of naproxen.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Antirreumáticos/efeitos adversos , Cicatriz/induzido quimicamente , Toxidermias/etiologia , Dermatoses Faciais/induzido quimicamente , Porfirias/induzido quimicamente , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Criança , Pré-Escolar , Cicatriz/epidemiologia , Toxidermias/epidemiologia , Dermatoses Faciais/epidemiologia , Feminino , Humanos , Lactente , Masculino , Naproxeno/efeitos adversos , Naproxeno/uso terapêutico , Porfirias/epidemiologia , Prevalência , Fatores de RiscoRESUMO
The role of thyroid status in hexachlorobenzene (HBC) induced porphyria was studied in normal, thyroidectomized and thyroxine (T4) treated rats. Female Wistar rats were treated with HCB for different periods of time. Serum T4 levels were depressed after 8 days of HCB administration whereas levels of triiodothyronine (T3) were not altered. T4 administered simultaneously with HCB resulted in hyperthyroxinemia. The time course of porphyrinogen carboxy-lyase (PCL) activity in the three HBC treated groups was studied. A rapid and significant decrease of PCL activity was found after 8 days of HCB treatment in T4 treated rats with respect to untreated animals. In contrast, HCB treatment of normal and thyroidectomized rats elicited a significant decrease of PCL activity after 21 and 30 days, respectively. This study shows that thyroid hormone plays an important role in the early establishment of HCB induced porphyria.
Assuntos
Porfirias/fisiopatologia , Tiroxina/farmacologia , Animais , Carboxiliases/análise , Feminino , Hexaclorobenzeno/toxicidade , Porfirias/induzido quimicamente , Porfirias/enzimologia , Ratos , Ratos Wistar , Tireoidectomia , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
1. The role of histidine on the decarboxylation of porphyrinogens of 7-, 6-, and 5-COOH III brought about by porphyrinogen carboxy-lyase (PCL) was studied. 2. For this purpose hepatic PCL from normal and hexachlorobenzene (HCB) treated rats were modified with diethylpyrocarbonate. 3. The results indicated that the enzyme from both normal and porphytic animals had histidine at the binding sites of all the porphyrinogens assayed. 4. Comparative studies between the enzyme from normal and porphyric rats suggested that in vivo HCB treatment affected the active site for the decarboxylation of 7-, 6- and 5-COOH porphyrinogens III at histidine residues. 5. On the other hand arginine modification by 2,3-butanedione treatment altered 5-COOH porphyrinogen III decarboxylation for both enzymes. However this amino acid was not involved at the binding site of this substrate.
Assuntos
Carboxiliases/metabolismo , Fígado/enzimologia , Animais , Arginina/química , Sítios de Ligação , Carboxiliases/química , Descarboxilação , Diacetil/farmacologia , Feminino , Hexaclorobenzeno/toxicidade , Histidina/química , Porfirias/induzido quimicamente , Porfirias/enzimologia , Porfirinogênios/química , Ratos , Ratos WistarRESUMO
Pseudoporphyria, a cutaneous disorder characterized by skin fragility, vesiculation, and scarring, has been reported as a side effect of naproxen therapy in children with juvenile rheumatoid arthritis (JRA). We report the results of a 6-month prospective study to determine the prevalence of pseudoporphyria in our JRA population. All the patients with pseudoporphyria had received naproxen for > or = 4 weeks at the time of the study. Of the patients treated with naproxen, 12% (9/74) developed this complication. No patient had significant elevation of free erythrocyte protoporphyrin, excluding the diagnosis of true erythropoietic protoporphyria. We conclude that pseudoporphyria is a common side effect of naproxen therapy in children with JRA, even in geographic areas without high sun exposure. Because of the risk of facial scarring with pseudoporphyria, physicians and parents of children with JRA should be aware of this complication.
Assuntos
Artrite Juvenil/tratamento farmacológico , Toxidermias/etiologia , Naproxeno/efeitos adversos , Porfirias/induzido quimicamente , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Naproxeno/uso terapêutico , Estudos ProspectivosRESUMO
Life threatening crisis may accompany some varieties of porphyria like the acute intermittent form, coproporphyria, porphyria variegata and that associated to deficiency of porphobilinogen synthetase. Drugs are commonly involved as precipitating factors. A classification of drugs according to their proven or probable triggering effect is offered in this paper. Insufficient information precludes the classification of some drugs.