Benznidazole-induced genotoxicity in diploid cells of Aspergillus nidulans

Abstract

Genotoxic effects of benznidazole were studied by the induction of homozygosis of genes previously present in heterozygous. UT448//A757 diploid strain was used in the benznidazole's recombinagenesis test. Although toxic effects on growth of colonies were not observed, 75 and 100 µM benznidazole induced an increasing of mitotic recombination events in diploid strain. Results were related to the induction of chromosomal breaks by the antiparasitic drug.Key words: benznidazole -somatic recombination -genotoxicity -homozigotization index Chagas disease, caused by Trypanosoma cruzi, is one of the most serious parasitic diseases of Latin America, where some 16 -18 million people are infected by the T. cruzi (WHO 1991). Although in Brazil the disease is under strict control, there are still about 4 million people infected by the parasite (Dias 1998). Benznidazole is used in the treatment of Chagas disease in the acute phase, at the start of the chronic phase, in congenital cases and accidental infection (Fragata Filho et al. 1997). Several adverse effects have been described in patients undergoing treatment with the anti-parasitic drug (Cançado 1997, Fragata Filho et al. 1997.The mutagenic action of the benznidazol has been studied in streptomycin-resistant Klebsiella pneumoniae strain and in Salmonella typhimurium TA100 strain. Mutagenic effect of the drug has also been observed in TA100 strain in the presence and in the absence of the microsomal hepatic fraction of mice, using 50 to 1000 µM concentrations (Voogd et al. 1975, Nagel & Nepomnaschy 1983.The mutagenic activity of benznidazole has also been determined in the simplified version of Ames test with sensitive (TA100 and TA102) and less sensitive (TA98 and TA97) S. typhimurium strains (Melo & Ferreira 1990) in the same plate. The drug's mutagenic effect was accounted to the interaction of reactive metabolites of benznidazole with the DNA and with nuclear proteins (Gorla et al. 1986, Zahoor et al. 1987, Ferreira et al. 1988).Benznidazole's genotoxicity has been studied in peritoneal macrophages of mice treated with benznidazole (Lacava & Luna 1994). These authors reported the clastogenic effect of the drug owing to increase in the frequency of chromatid breaks and to the formation of acrocentric chromosomes. Moya and Trombotto (1988) In spite of these contradictory results, the clastogenic effect of benznidazole (Lacava & Luna 1994) suggest its participation in the carcinogenic process due to the occurrence of mitotic crossing-over that induces the loss of heterozygosity of tumor suppressor genes (Zimmermann 1971, Weinberg 1991, Beumer et al. 1998. The evaluation of the recombinagenic potential of benznidazol in heterozygous cells of Aspergillus nidulans will be provided. Information on the participation of the anti-parasitic drug in the carcinogenesis process will be thus ensued. MATERIALS AND METHODSStrains and culture media -A. nidulans strains used are described in Table I. Minimum medium (MM) was Czape-Dox with 1% (w/v) glucose. Complete medium (CM) has pre...

Genotoxic Potentials of Natural Products Detected by a Short-Term Test Using Diploid Strains of Aspergillus nidulans

“…Despite such trends present shortterm test has been used to disclose suspected genotoxicity rapidly and efficiently. Besides, the test is very sensitive as genotoxicity can be detected even after application of low doses of a given agent, such as UV [13], benzene fumes [14], sodium nitroprusside [40], benznidazole [41], cisplatin and cytosine arabinoside [42] and X-ray [43]. These characters altogether allied to test inexpensiveness, suggest involved eukaryote microorganism (A. nidulans) can be proposed as a cell model to guide early approaches towards rapid screening of genotoxic potential and biological activities of many chemicals.…”

A Cysteine Protease Inhibitor Cures Chagas' Disease in an Immunodeficient-Mouse Model of Infection

“…Toxicity studies with nifurtimox noted neurotoxicity, testicular and ovarian damage, and deleterious effects in adrenal, colon, esophagus, and mammary tissues (6). Both drugs are potentially mutagenic and carcinogenic (23)(24)(25). Chemotherapy for Chagas' disease was traditionally recommended during the acute and indeterminate stages of infection (2,11,19), though recent treatment of chronically infected patients resulted in improved cardiac status (32).…”

Genotoxicity of the cyclo-oxygenase-inhibitor sulindac sulfide in the filamentous fungus Aspergillus nidulans

“…This happens because the initial selection process limits the growth of diploids -/-. Homozygotization Indexes (HI) (the ratio between prototrophic segregants and auxotrophic segregants), equal to or higher than 2.0, indicate the sulindac sulfide's recombinogenic effect (13). Results were compared by Yates correct Chi-square test.…”