Please use this identifier to cite or link to this item:
https://www.arca.fiocruz.br/handle/icict/63274
Type
ArticleCopyright
Restricted access
Embargo date
2025-12-31
Collections
Metadata
Show full item record
DELAYED GAMETOCYTE CLEARANCE IN <I>PLASMODIUM VIVAX</I> MALARIA IS ASSOCIATED WITH POLYMORPHISMS IN THE CYTOCHROME P450 REDUCTASE (CPR)
Plasmodium vivax
gametocytes
primaquine
pharmacogenetics
cytochrome P450 reductase
CYP2D6
Author
Affilliation
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal do Pará. Belém, PA, Brazil
Fundação Oswaldo Cruz Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brazil
Department of Microbiology. Tumor and Cell biology. Karolinska Institutet. Solna, Sweden
Fundação Oswaldo Cruz. Instituto René Rachou. Molecular Biology and Malaria Immunology Research Group. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Molecular Biology and Malaria Immunology Research Group. Belo Horizonte, MG, Brazil/ Department of Microbiology. Tumor and Cell biology. Karolinska Institutet. Solna, Sweden
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal de Roraima. Boa Vista, RO, Brazil
Universidade Federal do Pará. Belém, PA, Brazil
Fundação Oswaldo Cruz Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brazil
Department of Microbiology. Tumor and Cell biology. Karolinska Institutet. Solna, Sweden
Fundação Oswaldo Cruz. Instituto René Rachou. Molecular Biology and Malaria Immunology Research Group. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Molecular Biology and Malaria Immunology Research Group. Belo Horizonte, MG, Brazil/ Department of Microbiology. Tumor and Cell biology. Karolinska Institutet. Solna, Sweden
Abstract
Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in Plasmodium vivax malaria. It also has an effect on the gametocytes of Plasmodium falciparum; however, it is unclear to what extent PQ affects P. vivax gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with P. vivax malaria. To determine gametocyte density, we measured the levels of pvs25 transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the CPR mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation (P = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in pvs25 transcripts. Based on our findings, the CPR variant plays a role in the persistence of gametocyte density in P. vivax malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ–PQ treatment, particularly in settings and seasons of high Anopheles human-biting rates.
Keywords
malariaPlasmodium vivax
gametocytes
primaquine
pharmacogenetics
cytochrome P450 reductase
CYP2D6
Share