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Genotoxic effects of the antimalarial drug lumefantrine in human lymphocytes in vitro and computational prediction of the mechanism associated with its interaction with DNA
Author(s) -
de Lucca Renato M.R.,
Batista Júnior João,
Fontes Cor J. Fernandes,
de Oliveira Bahia Marcelo,
BassiBranco Carmen L.
Publication year - 2015
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.21942
Subject(s) - dna , micronucleus test , micronucleus , in vitro , mutagen , chemistry , docking (animal) , dna damage , biophysics , biology , microbiology and biotechnology , biochemistry , pharmacology , toxicity , medicine , nursing , organic chemistry
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. Environ. Mol. Mutagen. 56:556–562, 2015. © Wiley Periodicals, Inc.