Association of CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T Polymorphisms with Tacrolimus Dose, Serum Concentration, and Biochemical Parameters in Mexican Patients with Kidney Transplant.

Autor:	Alatorre-Moreno EV; Centro Universitario de Ciencias de la Salud, Departamento de Nefrología, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Universidad de Guadalajara, Guadalajara 44340, Mexico., Saldaña-Cruz AM; Centro Universitario de Ciencias de la Salud, Departamento de Fisiología, Instituto de Terapéutica Experimental y Clínica, Universidad de Guadalajara, Guadalajara 44340, Mexico., Pérez-Guerrero EE; Centro Universitario de Ciencias de la Salud, Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Guadalajara 44340, Mexico., Morán-Moguel MC; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico., Contreras-Haro B; Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá, UIB02, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Universidad de Guadalajara, Guadalajara 44340, Mexico., López-de La Mora DA; Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara 44340, Mexico., Dávalos-Rodríguez IP; Departamento de Biología Molecular y Genómica, División de Genética, Centro de Investigación Biomédica de Occidente, Centro Universitario de Ciencias de la Salud, Instituto Mexicano del Seguro Social, Universidad de Guadalajara; Guadalajara 44340, Mexico., Marín-Medina A; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico., Rivera-Cameras A; Departamento de Biología Molecular y Genómica, División de Genética, Centro de Investigación Biomédica de Occidente, Centro Universitario de Ciencias de la Salud, Instituto Mexicano del Seguro Social, Universidad de Guadalajara; Guadalajara 44340, Mexico., Balderas-Peña LA; Departamento de Morfología, Centro Universitario de Ciencias de la Salud, UIB02, Hospital de Especialidades Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Universidad de Guadalajara, Guadalajara 44340, Mexico., Gómez-Ramos JJ; Departamento de Urgencias, Hospital General de Zona 89, Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico., Cortés-Sanabria L; Centro Médico Nacional de Occidente, Hospital de Especialidades, Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico., Salazar-Páramo M; Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Academia de Inmunología, Universidad de Guadalajara, Guadalajara 44340, Mexico.
Jazyk:	angličtina
Zdroj:	Genes [Genes (Basel)] 2024 Apr 16; Vol. 15 (4). Date of Electronic Publication: 2024 Apr 16.
DOI:	10.3390/genes15040497
Abstrakt:	Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified in the genes encoding CYP3A4 , CYP3A5 , and ABCB1 , including CYP3A4-392A/G (rs2740574), CYP3A5 6986A/G (rs776746), and ABCB1 3435C/T (rs1045642). This study aims to evaluate the association among CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T polymorphisms and TAC, serum concentration, and biochemical parameters that may affect TAC pharmacokinetics in Mexican kidney transplant (KT) patients. Methods: Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and ABCB1 gene polymorphisms were genotyped using qPCR TaqMan. Serum TAC concentration (as measured) and intervening variables were assessed. Logistic regression analyses were performed at baseline and after one month to assess the extent of the association between the polymorphisms, intervening variables, and TAC concentration. Results: The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13-21.9; p = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54-93.08; p = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79-88.23; p = 0.018) were strongly associated with TAC pharmacokinetic variability. Conclusion: The findings of this study of the Mexican population showed that CYP3A5-6986 A/G GG genotype is associated with a four-fold increase in the likelihood of encountering a TAC concentration of more than 15 ng/dL. The co-occurrence of the CYP3A5-6986GG genotype and the use of drugs that increase TAC concentration correlates with a nine-fold increased risk of experiencing a TAC at a level above 15 ng/mL. Therefore, these patients have an increased susceptibility to TAC-associated toxicity.
Databáze:	MEDLINE
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