title: Genotoxic effects of the antimalarial drug lumefantrine in human lymphocytes in vitro and computational prediction of the mechanism associated with its interaction with DNA.
abstract: Lumefantrine (LF) is an aryl-amino alcohol antimalarial drug used in artemisinin-based combination therapies against malaria worldwide. In this study, we investigated the genotoxic effects of LF in human lymphocytes in vitro, and the potential noncovalent interaction of LF with DNA using a 3D DNA-docking model. The number of DNA breaks and the frequency of nuclear buds (NBUDS) was significantly increased (P < 0.01 and P < 0. 05, respectively) at LF concentrations of 60, 80, and 100 µg/mL (LF60, LF80, and LF100, respectively). Frequency (‰) of micronuclei (MN) formation also increased after LF treatments. However, this was only significant for LF100 (P = 0.01) and LF80 (P = 0.001). LF did not affect the frequency of nucleoplasmic bridges (NPBs) (P = 0.12) or the nuclear division index (NDI) (P = 0.32). Computational analysis suggests that LF may interact noncovalently with DNA via the DNA minor groove surface with a predicted binding affinity energy of -7.2 kcal/mol and showing a favorable shape complementary to this groove. Our results suggest that LF has clastogenic effects in human lymphocytes in vitro due to noncovalent interaction with the minor groove of DNA.
authors.affiliation: Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, Brazil.
authors.forename: Renato M R
authors.initials: RM
authors.lastname: de Lucca
authors.affiliation: Faculdade de Farmácia, Centro Universitário do Distrito Federal, Brasília, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: Batista Júnior
authors.affiliation: Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, Brazil.|Laboratório de Malária, Hospital Universitário Júlio Müller, Cuiabá, Brazil.
authors.forename: Cor J Fernandes
authors.initials: CJ
authors.lastname: Fontes
authors.affiliation: Pós-graduação em Neurociências e Biologia Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil.
authors.forename: Marcelo de Oliveira
authors.initials: Mde O
authors.lastname: Bahia
authors.affiliation: Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, Brazil.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Bassi-Branco
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000737:chemistry / Q000633:toxicity; D002478:Cells, Cultured; D020552:Comet Assay; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004983:Ethanolamines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005449:Fluorenes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D000078102:Lumefantrine; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D062105:Molecular Docking Simulation
chemical_list: D000962:Antimalarials; D004983:Ethanolamines; D005449:Fluorenes; D004247:DNA; D000078102:Lumefantrine
keywords: DNA minor groove agent; comet assay; computational analysis; malaria; micronucleus