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
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
In this paper, we studied the effect of heme availability on corticosterone and aldosterone synthesis in rat adrenal. We found that hemin stimulated corticosterone and aldosterone production in adrenal homogenates in a dose-dependent fashion. Hemin administration to rats also provoked an increase in both corticosterone and aldosterone content in adrenal. 3,5-Diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), an inhibitor of liver ferrochelatase activity, was able to inhibit this enzyme in rat adrenal. This resulted in an impairment of heme concentration and consequently adrenal ALA-synthase and porphyrin content were increased. Thus, it was proven that DDC inhibits heme biosynthesis in adrenal as it does in liver. In vivo experiments with rats showed that DDC was able to partially blocked ACTH-mediated corticosterone and aldosterone production while hemin administration was able to partially restore it. These data indicate that heme availability affects steroid biosynthesis in rat adrenal.