title: Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses.
abstract: Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Ana Carolina Rios
authors.initials: AC
authors.lastname: Silvino
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Gabriel Luiz
authors.initials: GL
authors.lastname: Costa
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Flávia Carolina Faustino de
authors.initials: FC
authors.lastname: Araújo
authors.affiliation: Biosystems Informatics Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.|Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David Benjamin
authors.initials: DB
authors.lastname: Ascher
authors.affiliation: Biosystems Informatics Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Douglas Eduardo Valente
authors.initials: DE
authors.lastname: Pires
authors.affiliation: Hospital Julio Muller, Universidade Federal de Mato Grosso, Cuiabá, Mato Grosso, Brazil.
authors.forename: Cor Jesus Fernandes
authors.initials: CJ
authors.lastname: Fontes
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Luzia Helena
authors.initials: LH
authors.lastname: Carvalho
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Cristiana Ferreira Alves de
authors.initials: CF
authors.lastname: Brito
authors.affiliation: Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Tais Nobrega
authors.initials: TN
authors.lastname: Sousa
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000378:metabolism / Q000627:therapeutic use; D002648:Child; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010966:Plasmodium vivax / Q000201:enzymology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011319:Primaquine / Q000378:metabolism / Q000627:therapeutic use; D012008:Recurrence; D055815:Young Adult
chemical_list: D000962:Antimalarials; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine