Silvino Ana Carolina Rios, Costa Gabriel Luiz, Araújo Flávia Carolina Faustino de, Ascher David Benjamin, Pires Douglas Eduardo Valente, Fontes Cor Jesus Fernandes, Carvalho Luzia Helena, Brito Cristiana Ferreira Alves de, Sousa Tais Nobrega
Molecular Biology and Malaria Immunology Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
Biosystems Informatics Research Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil.
PLoS One. 2016 Jul 28;11(7):e0160172. doi: 10.1371/journal.pone.0160172. eCollection 2016.
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.
虽然间日疟原虫复发通常与休眠子激活有关，但有人提出，其中一部分病例是由于细胞色素P-450 2D6（CYP2D6）基因多态性导致的伯氨喹（PQ）治疗失败所致。在此，我们提供证据表明，CYP2D6基因多态性与PQ治疗失败有关，这在基因相似的寄生虫研究结果中得到了加强，并且可能解释了一些间日疟复发的原因。通过计算方法预测，这些多态性可能通过改变结构稳定性来影响CYP2D6的活性，进而导致PQ与酶相互作用的破坏。此外，由于PQ与氯喹（CQ）联合使用，我们研究了细胞色素P-450 2C8（CYP2C8）对CQ代谢的损害是否也可能导致间日疟复发。我们的结果表明，携带CYP2C8突变的患者经常早期复发（<42天），并且基因相似的寄生虫比例更高，这表明可能由于CQ治疗失败导致再燃。这些结果凸显了药物遗传学研究作为监测抗疟治疗疗效工具的重要性。
