RESUMEN
Paraquat is still a widely used herbicide in several countries. Its toxic action on plants occurs through a one-electron reduction interfering with the photosynthesis process. By a similar reaction, the herbicide may induce peroxidation processes in non-target animal species. Furthermore, paraquat may interfere with the cellular transport of polyamines. The aim of this work was to investigate some aspects related to paraquat-induction of oxidative stress (lipoperoxidation, enzymatic activities of catalase and superoxide dismutase) and also the levels of polyamines (putrescine, spermidine and spermine) in two species of freshwater invertebrates, the oligochaete Lumbriculus variegatus and the gastropod Biomphalaria glabrata. The results showed that both organisms elicited differential responses. In addition, the data suggested that polyamines may play an important role against lipoperoxidation processes.
Asunto(s)
Biomphalaria/efectos de los fármacos , Herbicidas/toxicidad , Oligoquetos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Paraquat/toxicidad , Poliaminas/metabolismo , Animales , Biomphalaria/enzimología , Biomphalaria/metabolismo , Catalasa/metabolismo , Agua Dulce , Peroxidación de Lípido/efectos de los fármacos , Oligoquetos/enzimología , Oligoquetos/metabolismo , Putrescina/metabolismo , Espermidina/metabolismo , Espermina/metabolismo , Superóxido Dismutasa/metabolismo , Factores de TiempoRESUMEN
Hexachlorobenzene (HCB) alters phospholipid and heme metabolisms in the liver and Harderian gland. The effects of HCB on phospholipid metabolism, in an organ considered to be non-responsive to its porphyrinogenic effects, remain to be studied. Therefore, as the brain is an organ with this feature, this paper analyzes the effects of HCB on brain phospholipid composition in order to investigate if there is any relationship between HCB-induced porphyrin metabolism disruption and phospholipid alterations. For this purpose, a time-course study of HCB effects on brain phospholipids was performed in two strains of rats differing in their susceptibility to acquire hepatic porphyria: Chbb THOM (low); and Wistar (high). This paper shows for the first time that rat brain phospholipids are affected by HCB exposure. Comparative studies show that HCB-induced disturbances in brain phospholipid patterns are time and strain-dependent. Thus, whereas major phospholipids, phosphatidylcholine and phosphatidylethanolamine were more altered in Wistar rats, minor phospholipids, phosphatidylinositol and phosphatidylserine were more affected in Chbb THOM rats. HCB intoxication led to a sphingomyelin/phosphatidylcholine molar ratio lower than the normal, in both strains. As was expected, brain porphyrin content was not altered by HCB intoxication in either strain. It can be concluded that HCB is able to alter brain phospholipid metabolism in a strain-dependent fashion, and in the absence of alterations in brain heme metabolism. In addition, HCB-induced disturbances in brain phospholipids were not related to the degree of hepatic porphyria achieved by the rats.
Asunto(s)
Encéfalo/efectos de los fármacos , Hexaclorobenceno/farmacología , Fosfolípidos/metabolismo , Porfirinas/metabolismo , Esfingomielinas/antagonistas & inhibidores , Animales , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfatidilinositoles/agonistas , Fosfatidilinositoles/antagonistas & inhibidores , Fosfatidilserinas/antagonistas & inhibidores , Porfirias/metabolismo , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
Hexachlorobenzene (HCB) induces porphyria both in humans and rodents, and hepatocarcinoma in rodents. In a previous work we observed that HCB produces a continuous decrease in hepatic sphingomyelin (SM) content in Wistar rats. A distinguishing characteristic of sphingolipids breakdown products is their participation in anti-proliferative and apoptotic processes and in the suppression of oncogenesis. As a first step to elucidate the role of SM decrease in the hepatotoxicity induced by HCB, the present study evaluates the metabolic causes of the continuous decrease in hepatic SM content observed in Wistar rats with HCB intoxication, and its relation with porphyria development. For this purpose, the time-course (3, 7, 15, 21 and 28 days) of the effects of HCB on hepatic SM levels and on some of the enzymes of SM synthesis (serine palmitoyltransferase, SPT) and catabolism (sphingomyelinases, SMases) was followed, using two strains of rats differing in their susceptibility to acquire porphyria: Chbb THOM (low) and Wistar (high). HCB (1 g kg(-1) b.w. per day) was administered by gastric intubation as an aqueous suspension. After 5 days of HCB treatment, animals were allowed a 2-day recovery period without HCB administration. Two phases in the HCB-induced damages to sphingolipid metabolism were observed. The first stage (7 days of treatment), common to both strains of rats, was characterized by a decrease in hepatic SM levels (17-25%) and in SPT activity (50-43%), while strain differences were found for the later stage. In Chbb THOM rats, hepatic SM content was restored to normal values concomitantly with an increase in SPT activity (44%, at day 28), and without any increase in SM catabolism. In addition, the level of the other phospholipids was not altered. In Wistar rats, hepatic SM levels decreased continuously throughout the experiment, accompanied by increases in SPT, acidic sphingomyelinase (A-SMase) and neutral sphingomyelinase (N-SMase) activities (86, 28.5 and 78% increase, respectively). A role for glutathione (GSH) in the interstrain differences or a direct effect of HCB on SM metabolism was not found. The present study: (a) demonstrates that N-SMase, A-SMase, and SPT are some of the enzymes that play a role in the HCB-induced decrease of hepatic SM content; (b) finds that HCB-induced alterations of SM metabolism do not correlate with HCB-induced accumulation of hepatic porphyrins; and (c) proposes a link between HCB-induced alterations in phospholipid pattern and in SM metabolism. The increased SM hydrolysis produced as a consequence of SMases induction could be regarded as a cellular response to liver injury elicited by HCB, perhaps acting through the activation of SM signal transduction pathway delaying the proliferative processes observed after long-term treatment with HCB in some rodent species. However, such protective mechanism appears to be strain-dependent.
Asunto(s)
Aciltransferasas/efectos de los fármacos , Fungicidas Industriales/toxicidad , Hexaclorobenceno/toxicidad , Esfingomielina Fosfodiesterasa/efectos de los fármacos , Aciltransferasas/metabolismo , Animales , Femenino , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Fosfolípidos/metabolismo , Porfirinas/metabolismo , Ratas , Ratas Wistar , Serina C-Palmitoiltransferasa , Especificidad de la Especie , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Factores de TiempoRESUMEN
Hexachlorobenzene, one of the most persistent environmental pollutants, induces uroporphyria and phospholipid alterations in rat liver. Harderian glands produce a secretion that is rich in lipids and accumulate large amounts of protoporphyrin. The aim of the present study was to determine if hexachlorobenzene administration to rats affects phospholipid and porphyrin metabolisms in Harderian glands and if these effects are strain dependent. For this purpose, a time-course study (2, 3 and 4 weeks of hexachlorobenzene treatment) of phospholipid pattern and porphyrin content was performed comparatively in two strains of rats (Wistar and Chbb THOM) which differ in their susceptibility to develop HCB-induced porphyria. Hexachlorobenzene produced decreases in several phospholipid contents, but no changes in phosphatidylcholine levels. While the sphingomyelin/phosphatidylcholine molar ratio remained essentially constant until the third week in Chbb THOM rats, it showed a constant drop in Wistar rats, suggesting a more pronounced alteration of membrane fluidity in the later strain. In regard to porphyrin metabolism, Wistar rats showed an increase in the porphyrin content of the gland, while Chbb THOM animals showed a decrease. The study revealed that not only are the normal parameters of phospholipid and porphyrin metabolism in rat Harderian glands strain dependent, but the response to hexachlorobenzene is also.
Asunto(s)
Fungicidas Industriales/toxicidad , Glándula de Harder/efectos de los fármacos , Hexaclorobenceno/toxicidad , Fosfolípidos/metabolismo , Porfirinas/metabolismo , Animales , Femenino , Glándula de Harder/metabolismo , Ratas , Ratas Wistar , Especificidad de la Especie , Factores de TiempoRESUMEN
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.
Asunto(s)
Antineoplásicos/toxicidad , Dicarbetoxidihidrocolidina/toxicidad , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Porfirias/inducido químicamente , Alquilantes/toxicidad , Altretamina/toxicidad , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Azatioprina/toxicidad , Busulfano/toxicidad , Embrión de Pollo , Ciclofosfamida/efectos adversos , Ciclofosfamida/química , Ciclofosfamida/toxicidad , Dacarbazina/toxicidad , Femenino , Ferroquelatasa/efectos de los fármacos , Ferroquelatasa/metabolismo , Flavoproteínas , Fluorouracilo/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Mitocondriales , Oxidorreductasas/efectos de los fármacos , Oxidorreductasas/metabolismo , Porfirinas/metabolismo , Procarbazina/toxicidad , Protoporfirinógeno-Oxidasa , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Carcinoma Hepatocelular/enzimología , Dietilnitrosamina/uso terapéutico , Eritrocitos/metabolismo , Hidroximetilbilano Sintasa/metabolismo , Neoplasias Hepáticas/enzimología , Animales , Femenino , Hidroximetilbilano Sintasa/sangre , Masculino , RatasRESUMEN
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 (AU)
Asunto(s)
Animales , Masculino , Femenino , Ratas , Neoplasias Hepáticas/inducido químicamente , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina/uso terapéutico , Hidroximetilbilano Sintasa/metabolismo , Hidroximetilbilano Sintasa/sangreRESUMEN
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.
RESUMEN
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
Asunto(s)
Animales , Masculino , Femenino , Ratas , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina/uso terapéutico , Hidroximetilbilano Sintasa/metabolismo , Neoplasias Hepáticas/inducido químicamente , Hidroximetilbilano Sintasa/sangreRESUMEN
1. Some studies of cyclophosphamide (CP) and its metabolite acrolein in chick embryo liver were carried out in order to investigate the mechanism of the porphyrinogenic action of CP. 2. In vitro and in vivo studies revealed that CP induced but did not activate delta-aminolaevulinic acid (ALA) synthase. 3. Pretreatments with phenobarbital (PB) or SKF-525A did not modify ALA-synthase induction produced by CP. 4. Acrolein administration neither induced ALA-synthase activity nor increased cytochrome P-450 content or led to hepatic porphyrin accumulation. 5. Time course induction of cytochrome P-450 content after administration of CP or PB was similar. 6. The results obtained would indicate that CP is a strong inducer of both ALA-synthase activity and microsomal cytochrome P-450 content in liver of 17 day-old chick embryos and that its porphyrinogenic activity is not mediated by its metabolite acrolein.
Asunto(s)
Acroleína/farmacología , Embrión de Pollo/efectos de los fármacos , Ciclofosfamida/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Porfirinas/biosíntesis , 5-Aminolevulinato Sintetasa/metabolismo , Alilisopropilacetamida/farmacología , Animales , Embrión de Pollo/metabolismo , Ciclofosfamida/metabolismo , Sistema Enzimático del Citocromo P-450/biosíntesis , Sistema Enzimático del Citocromo P-450/metabolismo , Inducción Enzimática/efectos de los fármacos , Edad Gestacional , Hígado/química , Hígado/efectos de los fármacos , Hígado/enzimología , Estructura Molecular , Fenobarbital/farmacología , ProadifenoRESUMEN
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.
Asunto(s)
Hemo/metabolismo , Neoplasias Hepáticas Experimentales/enzimología , Porfirias/enzimología , Porfirinas/metabolismo , Caracteres Sexuales , 5-Aminolevulinato Sintetasa/metabolismo , Animales , Carboxiliasas , Sistema Enzimático del Citocromo P-450/metabolismo , Dietilnitrosamina , Femenino , Ferroquelatasa/metabolismo , Hexaclorobenceno , Hidroximetilbilano Sintasa/metabolismo , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Masculino , Porfirias/inducido químicamente , RatasRESUMEN
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.
Asunto(s)
Carcinoma Hepatocelular/complicaciones , Dietilnitrosamina/farmacología , Hexaclorobenceno/farmacología , Neoplasias Hepáticas/complicaciones , Porfirias/metabolismo , 5-Aminolevulinato Sintetasa/metabolismo , Ácido Aminolevulínico/orina , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Ferroquelatasa/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Porfobilinógeno/orina , Porfirias/etiología , Porfirinas/metabolismo , RatasRESUMEN
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.