Cytotoxic, mutagenic and genotoxic effects of new anti-T. cruzi 5-phenylethenylbenzofuroxans. Contribution of phase I metabolites on the mutagenicity induction

Toxicology Letters

Volumn 190, Issue 2, 2009, Pages 140-149

  Cabrera, Mauricio ^a   Lavaggi, María Laura ^a   Hernández, Paola ^a   Merlino, Alicia ^a   Gerpe, Alejandra ^a   Porcal, Williams ^a   Boiani, Mariana ^a   Ferreira, Ana ^a   Monge, Antonio ^b   de Cerain, Adela López ^b   González, Mercedes ^a   Cerecetto, Hugo ^a  

^a UNIVERSIDAD DE LA REPÚBLICA   (Uruguay)

^b UNIVERSITY OF NAVARRA   (Spain)

Author keywords

Benzofuroxan; Chagas' disease; Genotoxicity; Metabolism; Mutagenicity

Indexed keywords

(2 PHENYLETHENYL)BENZOFUROXAN; 5 PHENYLETHENYLBENZOFUROXAN DERIVATIVE; ANTIPROTOZOAL AGENT; CYTOCHROME P450; DRUG METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; UNCLASSIFIED DRUG; XANTHINE OXIDASE;

ANIMAL CELL; ARTICLE; CELL STRAIN CACO 2; CELL VIABILITY; CONTROLLED STUDY; CYTOSOL; CYTOTOXICITY; DRUG SAFETY; DRUG STRUCTURE; FEMALE; GENOTOXICITY; HUMAN; HUMAN CELL; LIVER HOMOGENATE; LIVER MICROSOME; LUNG FIBROBLAST; MACROPHAGE; MAMMAL CELL; MUTAGENICITY; NONHUMAN; PRIORITY JOURNAL; RAT; SALMONELLA TYPHIMURIUM; TRYPANOSOMA CRUZI;

ANIMALS; BENZOXAZOLES; BIOTRANSFORMATION; CELL SURVIVAL; COLORING AGENTS; COMET ASSAY; CRICETINAE; CYTOSOL; FEMALE; HUMANS; MICROSOMES, LIVER; MUTAGENICITY TESTS; MUTAGENS; RATS; RATS, WISTAR; SALMONELLA TYPHIMURIUM; TETRAZOLIUM SALTS; THIAZOLES; TRYPANOCIDAL AGENTS;

CRICETULUS GRISEUS; MAMMALIA; RATTUS; SALMONELLA TYPHIMURIUM; TRYPANOSOMA CRUZI;

EID: 69449084510     PISSN: 03784274     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.toxlet.2009.07.006     Document Type: Article

References (56)

1. Aguirre G., Boiani L., Boiani M., Cerecetto H., Di Maio R., González M., Porcal W., Denicola A., Piro O.E., Castellano E.E., Sant'Anna C.M.R., and Barreiro E.J. New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth. Quantitative structure-activity relationship studies. Bioorg. Med. Chem. 13 (2005) 6336-6346
2. Aguirre G., Boiani L., Cerecetto H., Di Maio R., González M., Porcal W., Thomson L., Tórtora V., Denicola A., and Möller M. Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitrypanosomal drugs. Part III. Substituents-clustering methodology in the search of new active compounds. Bioorg. Med. Chem. 13 (2005) 6324-6335
3. Aguirre G., Cerecetto H., Di Maio R., González M., Porcal W., Seoane G., Denicola A., Ortega M.A., Aldana I., and Monge-Vega A. Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitrypanosomal drugs. Structure-activity relationships. Part II. Arch. Pharm. 335 (2002) 15-21
4. Ames B.N., McCann J., and Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res. 31 (1975) 347-364
5. Atherton K.M., Mutch E., and Ford D. Metabolism of the soyabean isoflavone daidzein by CYP1A2 and the extra-hepatic CYPs 1A1 and 1B1 affects biological activity. Biochem. Pharmacol. 72 (2006) 624-631
6. Auwerx J. The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia 47 (1991) 22-31
7. Azqueta A., Pachón G., Cascante M., Creppy E.E., and López de Cerain A. A quinoxaline 1,4-di-N-oxide derivative induces DNA oxidative damage not attenuated by vitamin C and E treatment. Chem. Biol. Interact. 168 (2007) 95-105
8. Bartel L.C., Montalto de Mecca M., Fanelli S.L., Rodríguez de Castro C., Díaz E.G., and Castro J.A. Early nifurtimox-induced biochemical and ultrastructural alterations in rat heart. Hum. Exp. Toxicol. 26 (2007) 781-788
9. Boiani L., Davies C., Arredondo C., Porcal W., Merlino A., Gerpe A., Boiani M., Pacheco J.P., Basombrío M.A., Cerecetto H., and González M. In vivo studies of 5-arylethenylbenzofuroxans in acute murine models of Chagas' disease. Eur. J. Med. Chem. 43 (2008) 2229-2237
10. Boiani M., Merlino A., Gerpe A., Porcal W., Croce F., DePaula S., Rodríguez M.A., Cerecetto H., and González M. o-Nitroanilines as major metabolic products of anti-T. cruzi 5-phenylethenylbenzofuroxans in microsomal and cytosolic fractions of rat hepatocytes and in whole parasitic cells. Xenobiotica 39 (2009) 236-248
11. Brendler-Schwaab S., Hartmann A., Pfuhler S., and Speit G. The in vivo comet assay: use and status in genotoxicity testing. Mutagenesis 20 (2005) 245-254
12. Burlinson B., Tice R.R., Speit G., Agurell E., Brendler-Schwaab S.Y., Collins A.R., Escobar P., Honma M., Kumaravel T.S., Nakajima M., Sasaki Y.F., Thybaud V., Uno Y., Vasquez M., and Hartmann A. Fourth International Workgroup on Genotoxicity testing: results of the in vivo Comet assay workgroup. Mutat. Res. 627 (2007) 31-35
13. Castro J.A., and Díaz de Toranzo E.G. Toxic effects of Nifurtimox and Benznidazole, two drugs used against American Trypanosomiasis (Chagas disease). Biomed. Environ. Sci. 1 (1988) 19-33
14. Castro Silva R., Santiago C.M.G., Lima Pontes A., and Andrade S.G. Padrão isoenzimático da cepa Y do Trypanosoma cruzi após quimioterapia específica. Mem. Inst. Oswaldo Cruz 84 (1989) 81-86
15. Cerecetto H., Di Maio R., González M., Risso M., Saenz P., Seoane G., Denicola A., Peluffo G., Quijano C., and Olea-Azar C. 1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs. Structure-activity relationships. J. Med. Chem. 42 (1999) 1941-1950
16. Cerecetto H., and González M. Anti-T. cruzi agents: our experience in the evaluation of more than five hundred compounds. Mini Rev. Med. Chem. 8 (2008) 1355-1383
17. Cerecetto H., and González M. Chemotherapy of Chagaś disease: status and new developments. Curr. Top. Med. Chem. 2 (2002) 1187-1213
18. Chen L., Mei N., Yao L., and Chen T. Mutations induced by carcinogenic doses of aristolochic acid in kidney of Big Blue transgenic rats. Toxicol. Lett. 165 (2006) 250-256
19. Chu K.C., Patel K.M., Lin A.H., Tarone R.E., Linhart M.S., and Dunkel V.C. Evaluating statistical analysis and reproducibility of microbial mutagenicity assays. Mutat. Res. 85 (1981) 119-132
20. Chung Y.-T., Chen C.-L., Wu C.-C., Chan S.-A., Chi C.-W., and Liu T.-Y. Safrole-DNA adduct in hepatocellular carcinoma associated with betel quid chewing. Toxicol. Lett. 183 (2008) 21-27
21. Chung K.-T., Murdock C.A., Stevens S.E., Li Y.-S., Wei C.-I., Huang T.-S., and Chou M.W. Mutagenicity and toxicity studies of p-phenylenediamine and its derivatives. Toxicol. Lett. 81 (1995) 23-32
22. Collins A.R., Aiguo M., and Duthie S.J. The kinetics of repair of oxidative DNA damage (strand breaks and oxidized pyrimidines) in human cells. Mutat. Res. 336 (1995) 69-77
23. Collins A.R., Dusinska M., Franklin M., Somorovska M., Petrovska H., Fillion L., Panayiotidis M., Raslova K., and Vaughan N. Comet assay in human biomonitoring studies: reliability, validation, and applications. Environ. Mol. Mutagen. 30 (1997) 139-146
24. Crozet M.D., Botta C., Gasquet M., Curti C., Rémusat V., Hutter S., Chapelle O., Azas N., De Méo M., and Vanelle P. Lowering of 5-nitroimidazole's mutagenicity: towards optimal antiparasitic pharmacophore. Eur. J. Med. Chem. 44 (2009) 653-659
25. Da Silva Melo P., Duran N., and Haun M. Cytotoxicity of Prodigiosin and Benznidazole on V79 cells. Toxicol. Lett. 116 (2000) 237-242
26. De Andrade A.L.S.S., Zicker F., and De Oliveira R.M. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 348 (1996) 1407-1413
27. Gerpe A., Merlino A., Boiani M., Porcal W., Fagiolino P., González M., and Cerecetto H. Development of a HPLC method for the determination of antichagasic phenylethenylbenzofuroxans and its major synthetic secondary products in the chemical production processes. J. Pharm. Biomed. Anal. 47 (2008) 88-94
28. González-Martin G., Merino I., Rodríguez-Cabezas M.N., Torres M., Núñez R., and Osuna A. Characterization and trypanocidal activity of Nifurtimox-containing and empty nanoparticles of polyethylcyanoacrylates. J. Pharm. Pharmacol. 50 (1998) 29-35
29. Gorla N.B., Ledesma O.S., Barbieri G.P., and Larripa I.B. Thirteenfold increase of chromosomal aberrations nonrandomly distributed in chagasic children treated with Nifurtimox. Mutat. Res. 224 (1989) 263-267
30. Grosa G., Galli U., Rolando B., Fruttero R., Gervasio G., and Gasco A. Identification of 2,3-diaminophenazine and of o-benzoquinone dioxime as the major in vitro metabolites of benzofuroxan. Xenobiotica 34 (2004) 345-352
31. Ha-Duong N.T., Dijols S., Macherey A.C., Goldstein J.A., Dansette P.M., and Mansuy D. Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry 40 (2001) 12112-12122
32. Hartmann A., Agurell E., Beevers C., Brendler-Schwaab S., Burlinson B., Clay P., Collins A., Smith A., Speit G., Thybaud V., and Tice R.R. Recommendations for conducting the in vivo alkaline Comet assay. Mutagenesis 18 (2003) 45-51
33. Henderson L., Wolfreys A., Fedyk J., Bourner C., and Windebank S. The ability of the Comet assay to discriminate between genotoxins and cytotoxins. Mutagenesis 13 (1998) 89-94
34. Lavaggi M.L., Cabrera M., González M., and Cerecetto H. Differential enzymatic reductions governing the differential hypoxia-selective cytotoxicities of phenazine 5,10-dioxides. Chem. Res. Toxicol. 21 (2008) 1900-1906
35. Lee B.K., Kim J.H., Jung J.W., Choi J.W., Han R.S., Lee S.H., Ko K.H., and Ryu J.H. Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells. Toxicol. Lett. 157 (2005) 49-56
36. Liu Z., and Chen B. Caco-2 cell monolayers and it's application in toxicological research. Wei Sheng Yan Jiu 33 (2004) 756-759
37. Maron D.M., and Ames B.N. Revised methods for the Salmonella mutagenicity test. Mutat. Res. 113 (1983) 173-215
38. Moncayo A. Progreso en la interrupción de la enfermedad de Chagas en los países del cono sur. Medicina 59 Suppl. II (1999) 120-124
39. Montalto de Mecca M., Bartel L.C., Rodríguez de Castro C., and Castro J.A. Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects. Mem. Inst. Oswaldo Cruz 103 (2008) 549-553
40. Morton D.B., and Griffiths P.H.M. Guidelines on the recognition of pain, distress and discomfort in experimental animal and a hypothesis for assessment. Vet. Rec. 116 (1985) 431-436
41. Murta S.M.F., Gazzinelli R.T., Brener Z., and Romanha A.J. Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to Benznidazole and Nifurtimox. Mol. Biochem. Parasitol. 93 (1998) 203-214
42. Nagel R. Genotoxicity studies with two antichagasic drugs. Mutat. Res. 191 (1987) 17-20
43. Nozaki T., Engel J.C., and Dvorak J.A. Cellular and molecular biological analyses of Nifurtimox resistance in Trypanosoma cruzi. Am. J. Trop. Med. Hyg. 55 (1996) 111-117
44. Olea-Azar C., Rigol C., Mendizábal F., Briones R., Cerecetto H., Di Maio R., González M., Porcal W., and Risso M. Electrochemical and microsomal production of free radicals from 1,2,5-oxadiazole N-oxide as potential antiprotozoal drugs. Spectrochim. Acta Part A, Mol. Biomol. Spectrosc. 59 (2003) 69-74
45. Olea-Azar C., Rigol C., Mendizábal F., Cerecetto H., Di Maio R., González M., Porcal W., Morello A., Repetto Y., and Maya J.D. Novel benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as antichagasic agents: Chemical and biological studies. Lett. Drug Des. Disc. 2 (2005) 294-301
46. Olea-Azar C., Rigol C., Opazo L., Morello A., Maya J.D., Repetto Y., Aguirre G., Cerecetto H., Di Maio R., González M., and Porcal W. ESR and spin trapping studies of two new potential antitrypanosomal drugs. J. Chil. Chem. Soc. 48 (2003) 77-79
47. Porcal W., Hernández P., Aguirre G., Boiani L., Boiani M., Merlino A., Ferreira A., Di Maio R., Castro A., González M., and Cerecetto H. Second generation of 5-ethenylbenzofuroxan derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation and structure activity relationships. Bioorg. Med. Chem. 15 (2007) 2768-2781
48. Porcal W., Merlino A., Boiani M., Gerpe A., González M., and Cerecetto H. Arylethenylbenzofuroxan derivatives as drugs for Chagas disease: multigram batch synthesis using a Wittig-Boden process. Org. Process Res. Dev. 12 (2008) 156-162
49. Souza S.C., Takahashi C.S., and Da Silva J.S. Evaluation of the mutagenic potential of the drug Rochagan in healthy and chagasic rodents. Mutat. Res. 259 (1991) 139-145
50. Sun Z.-Y., Botros E., Su A.-D., Kim Y., Wang E., Baturay N.Z., and Kwon C.-H. Sulfoxide-containing aromatic nitrogen mustards as hypoxia-directed bioreductive cytotoxins. J. Med. Chem. 43 (2000) 4160-4168
51. Teixeira A.R.L., Silva R., Cunha Neto E., Santana J.M., and Rizzo L.V. Malignant, non-Hodgkins' lymphomas in Trypanosoma cruzi-infected rabbits treated with nitroarenes. J. Comp. Pathol. 103 (1990) 37-48
52. Teixeira A.R.L., Calixto M.A., and Teixeira M.L. Chagas' disease carcinogenic activity of the antitrypanosomal nitroarenes in mice. Mutat. Res. 305 (1994) 189-196
53. Tice R.R., Agurell E., Anderson D., Burlinson B., Hartmann A., Kobayashi H., Miyamae Y., Rojas E., Ryu J.C., and Sasaki Y.F. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ. Mol. Mutagen. 35 (2000) 206-221
54. WHO/TDR, 2005. Report of the Scientific Working Group on Chagas Disease.
55. Yun C.-H., Lee H.S., Lee H.-Y., Yim S.-K., Kim K.-H., Kim E., Yea S.-S., and Guengerich F.P. Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin. Toxicol. Lett. 137 (2003) 143-150
56. Zhang Z., Che W., Liang Y., Wu M., Li N., Shu Y., Liu F., and Wu D. Comparison of cytotoxicity and genotoxicity induced by the extracts of methanol and gasoline engine exhausts. Toxicol. In Vitro 21 (2007) 1058-1065