title: Genotoxic evaluation of five Angiotesin II receptor blockers: in vivo and in vitro micronucleus assay.
abstract: Angiotensin II receptor blockers (ARBs) are a new class of drugs for the treatment of hypertension. In this study, we studied the potential genotoxic effects of five ARBs in vivo and in vitro in human peripheral blood lymphocytes (PBLs) by means of the cytokinesis-block micronucleous (CBMN) assay in combination with fluorescence in situ hybridization (FISH) with a centromeric probe. The nuclear division index (NDI) was used as a measure of cytotoxicity. We also analyzed the association between sex, age, duration of treatment and MN formation. The in vivo study was carried out in 55 hypertensive patients. The in vitro study was performed in 10 control individuals by adding the drugs to the culture medium at a final concentration similar to the levels found in plasma in patients. Our results showed a significant increase in the frequencies of MN and binucleated cells with MN (BNMN) in vivo and especially in vitro. We observed variability in the mean frequency of MN and BNMN among the five drugs analyzed. In vivo, patients treated with Candesartan, Telmisartan and Valsartan showed a statistical significant increase in these parameters, while Olmesartan showed the highest effect in vitro. We also found that the drugs inhibit the NDI in vitro and that Eprosartan, Olmesartan and Telmisartan are the ARBs studied with the highest effect in decreasing the proliferation of the cells. FISH analysis revealed no significant difference between patients and controls in the frequency of centromeric signals. A slight variability, without statistical significance, in the frequency of micronuclei with a centromere signal (CN(+)MN) was found among the different ARBs analyzed, ruling out an aneugenic potential. When accounting for risk factors, we found that in patients there is a positive correlation between MN, BNMN and sex and a negative correlation with duration of treatment.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Bilbao, Spain; Genetic Laboratory, Bilbao, Spain.
authors.forename: Iratxe
authors.initials: I
authors.lastname: Huerta
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Bilbao, Spain.
authors.forename: Maitane
authors.initials: M
authors.lastname: Barasoain
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Bilbao, Spain; Genetic Laboratory, Bilbao, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Télez
authors.affiliation: Virgen de Begoña Laboratories (Medikosta), Erandio, Bizkaia, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Longa
authors.affiliation: Virgen de Begoña Laboratories (Medikosta), Erandio, Bizkaia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Muga
authors.affiliation: Department of Medical-Surgical Specialties, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Barrenetxea
authors.affiliation: Department of Medical-Surgical Specialties, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortiz-Lastra
authors.affiliation: Department of Medical-Surgical Specialties, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González
authors.affiliation: Cooperativa de Ensino Superior Politecnico e Universitario (CESPU), Porto, Portugal.
authors.forename: Begoña
authors.initials: B
authors.lastname: Criado
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, Bilbao, Spain. Electronic address: mariaisabel.arrieta@ehu.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Arrieta
mesh_terms: D000368:Aged; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D008875:Middle Aged
chemical_list: D057911:Angiotensin Receptor Antagonists
keywords: Angiotensin II receptor blockers; FISH; Genotoxicity; Micronuclei