Absence of the human CYP2C8*3 allele in Ugandan children exposed to Plasmodium falciparum malaria

Paganotti, Giacomo Maria; Cosentino, V.; Russo, Gianluca; Tabacchi, Francesca; Gramolelli, Silvia; Cóluzzi, M.; Romano, Rita

doi:10.1016/j.meegid.2014.08.011

Cited by 3 publications

(4 citation statements)

References 30 publications

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“…This finding is not surprising since this variant allele has been shown to be rare/uncommon among indigenous Africans and predominantly concentrated in Caucasians [14]. CYP2C8*3 frequencies recorded in this study are similar to Uganda [61] and other African countries [50]. …”

Section: Discussionsupporting

confidence: 78%

Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations

Marwa

Schmidt

Sjögren

et al. 2014

Malar J

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BackgroundArtemisinin-based combinations currently recommended for treatment of uncomplicated Plasmodium falciparum malaria in many countries of sub-Saharan Africa are substrates of CYP enzymes. The cytochrome enzyme system is responsible for metabolism of about 80-90% of clinically used drugs. It is, therefore, important to obtain the pharmacogenetics of the population in the region with respect to these combinations and thereby enable practitioners to predict treatment outcomes. The aim of this study was to detect and determine allelic frequencies of CYP2C8*2, CYP2C8*3, CYP3A4*1B, CYP3A5*3 and CYP2B6*6 variant alleles in a Tanzanian indigenous population.MethodsGenomic DNA extraction from blood obtained from 256 participants who escorted patients at Karume Health Centre in Mwanza Tanzania, was carried out using the Gene JET™ Genomic DNA purification kit (Thermo Scientific). Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. Amplification was done by PCR while differentiation between alleles was done by restriction fragment length polymorphism (PCR-RFLP) (for CYP2C8*2, CYP2C8*3) and sequencing (for CYP2B6*6, CYP3A5*3 and CYP3A4*1B).ResultsCYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A4*1B and CYP2B6*6 variant allelic frequencies were found to be 19,10,16,78 and 36% respectively.ConclusionPrevalence of CYP2C8*2, CYP3A5*3, CYP3A4*1B and CYP2B6*6 mutations in a Tanzanian population/subjects are common. The impact of these point mutations on the metabolism of anti-malarial drugs, particularly artemisinin-based combinations, and their potential drug-drug interactions (DDIs) needs to be further evaluated.

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Section: Discussionsupporting

confidence: 78%

Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations

Marwa

Schmidt

Sjögren

et al. 2014

Malar J

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“…A study conducted in Burkina Faso demonstrated that P. falciparum chloroquine-resistant alleles, Pfcrt 76T and Pfmdr1 86Y, were associated with the CYP2C8*2 allele (Paganotti et al, 2011). Other studies from East Africa have reported incongruent findings possibly due to high chloroquine-resistant allele frequency (Paganotti et al, 2014;Cavaco et al, 2013). In view of this, Paganotti et al postulated that drug-resistant parasites may be selected based on CYP2C8*2 at lower drug resistance levels (Paganotti et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies from East Africa have reported incongruent findings possibly due to high chloroquine-resistant allele frequency (Paganotti et al, 2014;Cavaco et al, 2013). In view of this, Paganotti et al postulated that drug-resistant parasites may be selected based on CYP2C8*2 at lower drug resistance levels (Paganotti et al, 2014). Since chloroquine metabolism is dependent on more than one CYP, it is difficult to investigate the role of CYP2C8*2 in the emergence chloroquine-resistant parasites.…”

Section: Discussionmentioning

confidence: 99%

Distribution of the cytochrome P450 CYP2C8*2 allele in Brazzaville, Republic of Congo

Peko

Ntoumi

Vouvoungui

et al. 2019

International Journal of Infectious Diseases

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Background: Cytochrome P450 (CYP) enzymes are essential in the metabolism of most drugs used today. Single nucleotide polymorphism(s) occurring in CYP genes can adversely affect drug pharmacokinetics, efficacy, and safety. Individuals carrying the CYP2C8*2 c.805A > T (CYP2C8*2; rs11572103) allele have impaired amodiaquine metabolism, increased risk of amodiaquine-related adverse events, and may promote the selection of drug-resistant parasite strains. This study investigated the distribution of the CYP2C8*2 allele in Brazzaville, Republic of Congo, where artesunate + amodiaquine is used as the secondline treatment for uncomplicated Plasmodium falciparum malaria. Methods: A total of 285 febrile children visiting the Marien Ngouabi paediatric hospital were genotyped for CYP2C8*2 using PCR-restriction fragment length polymorphism (PCR-RFLP). The allele frequencies and genotype distribution were determined. Results: The CYP2C8*2 allele was successfully genotyped in 75% (213/285) of the study participants. The CYP2C8*2A allele had a frequency of 63%, whereas the CYP2C8*2T allele had a frequency of 37%. Genotypes CYP2C8*2AA (rapid metabolizer), CYP2C8*2AT (intermediate metabolizer), and CYP2C8*2TT (poor metabolizer) were observed in 44%, 38%, and 18% of the investigated participants, respectively. Conclusions: This study gives the first description of CYP2C8*2 allele distribution in the Republic of Congo and highlights the potential risk of amodiaquine-related adverse events. Information from this study will be beneficial during pharmacovigilance investigations.

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“…In the mixed Brazilian and Ecuadorian populations, its frequency is 0.08 and 0.07, and in a Chilean mestizo population it is 0.06 (Roco et al, 2012;Suarez-Kurtz et al, 2012;Vicente et al, 2014). There is wide variability in the frequency of CYP2C8*3 in sub-Saharan African populations, even within a country (Cavaco et al, 2005;Rower et al, 2005;Parikh et al, 2007;Kudzi et al, 2009;Arnaldo et al, 2013;Staehli Hodel et al, 2013;Marwa et al, 2014;Paganotti et al, 2014). For example, the frequency of CYP2C8*3 was found to be 0.00 in individuals in central Tanzania and as high as 0.10 in the Mwanza region of Tanzania (Staehli Hodel et al, 2013;Marwa et al, 2014).…”

Section: A Population Geneticsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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Absence of the human CYP2C8*3 allele in Ugandan children exposed to Plasmodium falciparum malaria

Cited by 3 publications

References 30 publications

Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations

Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations

Distribution of the cytochrome P450 CYP2C8*2 allele in Brazzaville, Republic of Congo

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

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