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Pharmacogenetics of Praziquantel Metabolism: Evaluating the Cytochrome P450 Genes of Zimbabwean Patients During a Schistosomiasis Treatment.

ABSTRACT: Schistosomiasis is a parasitic disease infecting over 236 million people annually, with the majority affected residing on the African continent. Control of this disease is reliant on the drug praziquantel (PZQ), with treatment success dependent on an individual reaching PZQ concentrations lethal to schistosomes. Despite the complete reliance on PZQ to treat schistosomiasis in Africa, the characterization of the pharmacogenetics associated with PZQ metabolism in African populations has been sparse. We aimed to characterize genetic variation in the drug-metabolising cytochrome P450 enzymes (CYPs) and determine the association between each variant and the efficacy of PZQ treatment in Zimbabwean patients exposed to Schistosoma haematobium infection. Genomic DNA from blood samples of 114 case-control Zimbabweans infected with schistosomes were sequenced using the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genes as targets. Bioinformatic tools were used to identify and predict functional effects of detected single nucleotide polymorphisms (SNPs). A random forest (RF) model was then used to assess SNPs most predictive of PZQ efficacy, with a misclassification rate of 29%. SNPs were detected across all six genes, with 70 SNPs identified and multiple functional changes to the CYP enzymes predicted. Only four SNPs were significantly associated with PZQ efficacy using χ² tests, with rs951840747 (OR: 3.61, p = 0.01) in the CYP1A2 gene having the highest odds of an individual possessing this SNP clearing infection, and rs6976017 (OR: 2.19, p = 0.045) of CYP3A5 determined to be the most predictive of PZQ efficacy via the RF. Only the rs28371702 (CC) genotype (OR: 2.36, p = 0.024) of CYP2D6 was significantly associated with an unsuccessful PZQ treatment. This study adds to the genomic characterization of the diverse populations in Africa and identifies variants relevant to other pharmacogenetic studies crucial for the development and usage of drugs in these populations.

SUBMITTER: Zdesenko G

PROVIDER: S-EPMC9213834 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4-12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.

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Pharmacogenetics of Praziquantel Metabolism: Evaluating the Cytochrome P450 Genes of Zimbabwean Patients During a Schistosomiasis Treatment.

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