RESUMO
Azathioprine (Aza) is a purine antimetabolite immunosuppressant that is widely employed for immunosuppressive therapy in post-transplant recipients or patients with autoimmune diseases. Chronic use of immunosuppressants might produce several side effects, including a high rate of neoplasms in these patients. Considering that genotoxic effects are associated with an increased risk of developing cancer, the aim of this study was to examine the recombinogenic, genotoxic, and cytotoxic effects of Aza using Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster, as well as comet and micronucleus assays in mouse bone marrow cells. Further, the adverse effects of Aza were determined in mouse hepatic and renal tissues using histopathological analysis. Data demonstrated that Aza induced significant increased genotoxicity in D. melanogaster and mouse bone marrow cells at all concentrations tested. Homologous recombination was the predominant genotoxic event noted for the first time to be initiated by Aza in SMART. In histopathological analysis, Aza did not show any marked toxic activity in mouse hepatic and renal tissues. Therefore, the high rate of neoplasms reported in patients with long-term use of Aza may be attributed, at least partially, to the genotoxic action of this drug.
Assuntos
Azatioprina/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Imunossupressores/toxicidade , Animais , Células da Medula Óssea/efeitos dos fármacos , Ensaio Cometa , Camundongos , Testes para Micronúcleos , Testes de MutagenicidadeRESUMO
Este relato teve como objetivo apresentar um caso de hepatotoxicidade colestática induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada. À admissão, apresentava icterícia +3/+4, acolia fecal e colúria, além de aumento de marcadores hepáticos, sendo compatível com síndrome colestática, cuja etiologia foi confirmada após exclusão de outras causas possíveis e retirada da azatioprina. A paciente evoluiu, após 1 semana de retirada do fármaco, com diurese livre de coloração menos escura e evacuação presente, sem acolia. Além disso, houve melhora nos exames que precederam a alta hospitalar
This report aimed at presenting a case of azathioprine-induced cholestatic hepatotoxicity in a patient with Vogt-Koyanagi-Harada syndrome. On admission, she presented with jaundice +3/+4, acholic feces, and choluria, as well as increased hepatic markers, all consistent with cholestatic syndrome, the etiology of which was confirmed after other possible causes were ruled out and azathioprine was discontinued. After 1 week of the drug discontinuation, the patient progressed with free diuresis of lighter color and defecation, with no acholia. In addition, tests performed before discharge were improved.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Azatioprina/toxicidade , Azatioprina/uso terapêutico , Síndrome Uveomeningoencefálica/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Imunossupressores/toxicidade , Imunossupressores/uso terapêutico , Sinusite/tratamento farmacológico , Azatioprina/efeitos adversos , Tórax/diagnóstico por imagem , Radiografia , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/sangue , Ultrassonografia , Pneumonia Bacteriana/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/sangue , Bócio Nodular/diagnóstico por imagem , Imunossupressores/efeitos adversos , Antibacterianos/uso terapêuticoRESUMO
Os nucleotídeos de tioguanina (6-TGN), metabólitos ativos da azatioprina (AZA) e da 6-mercaptopurina (6-MP), atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT), está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP) e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.
Thioguanine nucleotides (6-TGN), active metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP), act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT) is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP) and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.
Assuntos
Humanos , Azatioprina/administração & dosagem , Azatioprina/farmacocinética , Azatioprina/metabolismo , Azatioprina/toxicidade , Azatioprina/uso terapêutico , Monitoramento de Medicamentos , /farmacologia , Tioguanina/farmacologiaRESUMO
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 immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-thiouric acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites. We analyzed TPMT activity in erythrocyte lysates of 25 controls, 25 uremic patients on dialysis, and 68 transplanted patients. Median activity was lower in controls (31.0 pmol/hr/mg Hb, range 16.2-43.0) and transplanted patients receiving only cyclosporine and prednisolone (31.7 pmol/hr/mg Hb, range 12.7-43.5) than in the azathioprine treated group, (36.1 pmol/hr/mg Hb, range 16.1-71.3), or the uremic group on dialysis, (35.5 pmol/hr/mg Hb, range 18.6-62.6) suggesting that both azathioprine and uremia induce the enzyme, but CsA does not. Only 3 patients demonstrated total intolerance to azathioprine, 2 of whom had very low TPMT activity (zero and 12.7 pmol/hr/mg Hb). The intolerance of the third patient, despite high TPMT activity, was attributed to concomitant cotrimoxazole therapy. Patients with intermediate activity (15-26 pmol/hr/mg Hb) could tolerate azathioprine well. Of 29 cadaver recipients given only azathioprine plus prednisolone, 24 with a better clinical outcome had a significantly lower activity (33.1 pmol/hr/mg Hb, range 16.1-46.1) than 5 with reduced allograft function (42.5 pmol/hr/mg Hb, range 33.8-51.5). TPMT activity in these 24 patients was also significantly lower than the general group of azathioprine-treated recipients. This inverse association between TPMT activity and allograft function was again found among 30 patients receiving triple therapy (azathioprine, CsA, prednisolone). Self-selection of the best recipients for azathioprine immunosuppression apparently occurred, based on low catabolism of the drug. We conclude that total intolerance to azathioprine is rare and usually appears in patients with very low TPMT activities. Our results also suggest that the wide range of TPMT activity may be an important factor in determining long-term graft survival in azathioprine-treated patients; those with high activity might benefit from doses near the upper limit generally recommended.
Assuntos
Azatioprina/uso terapêutico , Transplante de Rim/imunologia , Metiltransferases/metabolismo , Adolescente , Adulto , Idoso , Azatioprina/toxicidade , Criança , Ciclosporina/uso terapêutico , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Testes de Função Renal , Contagem de Leucócitos , Masculino , Metiltransferases/sangue , Pessoa de Meia-Idade , Prednisolona/uso terapêuticoRESUMO
A report is presented of the effects upon the liver and enteric mucosa of rats treated chronically with azathioprine (AZA) and cyclophosphamide (CY) in equiactive doses three times greater. The groups treated either with equiactive doses of AZA and CY or with doses three times greater of AZA and CY presented limited and moderate morphological alteration in the liver and in the mucosa of the small intestine, while all rats treated with high dose of CY died in the first phase of the experiment.