RESUMO
Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.
Assuntos
Fármacos Anti-HIV/toxicidade , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Dano ao DNA , Lamivudina/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Zidovudina/toxicidade , Animais , Células CHO , Cricetulus , Lamivudina/administração & dosagem , Mutagênese , Mutação , Zidovudina/administração & dosagemRESUMO
In order to investigate the effects of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the DNA damage in vivo, nevirapine (NVP; 3.3 mg/kg), efavirenz (EFV; 10 mg/kg) or saline were administered orally. Acute effects were analyzed 24 h after the administration of a single NNRTI dose, and subchronic effects 24 h after the last dose. Peripheral blood, brain, heart and liver samples were subjected to genotoxicity analyses and polychromatic erythrocytes from the bone marrow to micronucleus test. The micronucleus test did not reveal any significant differences between animals from the acute or subchronic groups. Comet assay showed that acute and subchronic NNRTI treatment did not cause any significant DNA damage in heart, liver or peripheral blood cells. However, increased damage indexes and frequencies were observed in the brain of mice, subchronically treated with EFV. This result suggests for the first time that this drug might induce genotoxicity in the brain.
Assuntos
Fármacos Anti-HIV/toxicidade , Benzoxazinas/toxicidade , Nevirapina/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Alcinos , Animais , Células da Medula Óssea/citologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ensaio Cometa , Ciclopropanos , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Fígado/citologia , Masculino , Camundongos , Testes para Micronúcleos , Miocárdio/citologiaRESUMO
IMPORTANCE OF THE FIELD: The nucleoside reverse transcriptase inhibitors (NRTIs) are used in antiretroviral therapy worldwide for the treatment of HIV infections. These drugs act by blocking reverse transcriptase enzyme activity, causing pro-viral DNA chain termination. As a consequence, NRTIs could cause genomic instability and loss of heterozygosity. AREAS COVERED IN THIS REVIEW: This review highlights the toxic and genotoxic effects of NRTIs, particularly lamivudine (3TC) and stavudine (d4T) analogues. In addition, a battery of short-term in vitro and in vivo systems are described to explain the potential genotoxic effects of these NRTIs as a single drug or a complexity of highly active antiretroviral therapy. WHAT THE READER WILL GAIN: The readers will gain an understanding of a secondary effect that could be induced by 3TC and d4T treatments. TAKE HOME MESSAGE: Considering that AIDS has become a chronic disease, more comprehensive toxic genetic studies are needed, with particular attention to the genetic alterations induced by NRTIs. These alterations play a primary role in carcinogenesis and are also involved in secondary and subsequent steps of carcinogenesis.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Aberrações Cromossômicas/efeitos dos fármacos , Lamivudina/efeitos adversos , Mutação , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Adulto , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Criança , Ensaios Clínicos como Assunto , Cricetinae , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Haplorrinos , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/toxicidade , Camundongos , Testes de Mutagenicidade , Ratos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Estavudina/administração & dosagem , Estavudina/farmacocinética , Estavudina/toxicidadeRESUMO
Lamivudine (3TC) and stavudine (d4T) are nucleoside analogue reverse transcriptase inhibitors employed in antiretroviral therapies. The mutational and recombinational potential as well as the total genetic toxicity was determined for both compounds at concentrations allowing at least 30% survival using the standard version of wing SMART assay. The standardized clone induction frequency per mg/ml for mwh/flr(3) genotype were approximately 2 and approximately 33 mutant clones/10(5) cells/(mg/ml) for d4T and 3TC, respectively. Comparing these results with those obtained in the mwh/TM3 genotype, it was possible to quantify the recombinagenic action of each drug. Approximately 86% of the mutant clones induced by 3TC and approximately 76% of the d4T induced clones were related to their mitotic recombination action. Our results indicate that both 3TC and d4T have high recombinagenic potential, and suggest that exposure to the drugs could cause genomic instability and loss of heterozygosity. This may be due to the fact that these genetic alterations play a primary role in carcinogenesis, and are also involved in secondary and subsequent steps of carcinogenesis by which recessive oncogenic mutations are revealed.
Assuntos
Drosophila melanogaster/efeitos dos fármacos , Lamivudina/toxicidade , Mutagênicos/toxicidade , Recombinação Genética/efeitos dos fármacos , Inibidores da Transcriptase Reversa/toxicidade , Estavudina/toxicidade , Animais , Drosophila melanogaster/genéticaRESUMO
Antiretroviral therapies based on nucleoside reverse transcriptase inhibitors, like zidovudine (3'-azido-3'-deoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI), markedly reduce human immunodeficiency virus loads. The Somatic Mutation And Recombination Test in Drosophila melanogaster (wing SMART), in its standard version, was applied to compare AZT and ddI genetic toxicity expressed as point and chromosomal mutation as well as homologous mitotic recombination. The present findings provide evidence that the mechanistic basis underlying the genetic toxicity of these antiretrovirals is mainly related to mitotic recombination. However, a genotoxic pattern can correspondingly be discerned: AZT is able to induce recombination ( approximately 85%) and mutation ( approximately 15%), and ddI causes only homologous recombination (100%) in the wing SMART assay. Another point to be considered is the fact that ddI is 3.8 times less active to induce mutant clones per mg/ml unit as compared to AZT. The clinical significance of these observations has to be interpreted in the light of data obtained from long-term toxicity in patients treated with the above mentioned agents.