Distribution of CYP3A4 and CYP3A5 Polymorphisms and Genotype Combination Implicated in Tacrolimus Metabolism

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Published Aug 27, 2024
https://doi.org/10.62438/tunismed.v102i9.4969
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Vol. 102 No. 9 (2024): Tunis Med sept 2024

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Ibtissem Hannachi
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
Zohra Chadli
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
Emna Kerkeni
Laboratory of Genetics, Faculty of Medicine, University of Monastir, Tunisia
Amel Chaabane
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
Nadia Ben Fredj
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
Naceur Boughattas
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
Karim Aouam
Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia

Abstract

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Introduction: Human cytochrome P450 (CYP), particularly CYP3A4 and CYP3A5 is mainly responsible for the metabolism of several drugs including tacrolimus. Significant interracial/interethnic variation in the expression and function of CYP3A5 and CYP3A4 is caused by Single Nucleotide Polymorphisms (SNPs) of genes encoding these proteins.


Aim: The present study investigated the genetic polymorphisms CYP3A4*1B, CYP3A4*22, and CYP3A5*3 in the Tunisian population.


Methods: We included in this study, Tunisian healthy subjects and renal transplant recipients receiving tacrolimus. CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). According to the genotypic combination of the three CYP polymorphisms, we have identified for the first time four metabolizers statuses: slow metabolizers (SM), intermediate metabolizers (IM), high metabolizers (HM), and extensive metabolizers (EM).


Results: A total of 101 renal transplant patients and 102 healthy subjects were included. Our results showed that the predominant alleles in the Tunisian population are a wild type of CYP3A4*1B (0.87), likewise CYP3A4*22 (0.975) and CYP3A5*3 (0.82). The genotype frequencies of CYP3A4*1B, CYP3A4*22, and CYP3A5*3 were found to be 3.9%, 0.0%, and 69.5%, respectively. Also, we found a significant linkage disequilibrium between CYP3A4*1B and CYP3A5*3. We approved that the IM is the predominant phenotype in our population with 124 patients followed by and EM with 41 patients, HM in 29 patients and SM in 9 patients. These results showed that Tunisians are most similar to Caucasians. Conclusion: The genetic background of these enzymes CYP3A4*1B, CYP3A4*22, and CYP3A5*3 ...(abstract  truncated at 250 words).

Keywords:

CYP3A4*1B, CYP3A4*22, CYP3A5*3, tacrolimus, Pharmacogenetics, Tunisian Population

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