Alatorre-Moreno Edith Viridiana, Saldaña-Cruz Ana Miriam, Pérez-Guerrero Edsaúl Emilio, Morán-Moguel María Cristina, Contreras-Haro Betsabé, López-de La Mora David Alejandro, Dávalos-Rodríguez Ingrid Patricia, Marín-Medina Alejandro, Rivera-Cameras Alicia, Balderas-Peña Luz-Ma Adriana, Gómez-Ramos José Juan, Cortés-Sanabria Laura, Salazar-Páramo Mario
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.
Centro Universitario de Ciencias de la Salud, Departamento de Fisiología, Instituto de Terapéutica Experimental y Clínica, Universidad de Guadalajara, Guadalajara 44340, Mexico.
Genes (Basel). 2024 Apr 16;15(4):497. doi: 10.3390/genes15040497.
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 , , and , 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.
Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and 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.
The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13-21.9; = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54-93.08; = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79-88.23; = 0.018) were strongly associated with TAC pharmacokinetic variability.
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.
他克莫司（TAC）是一种免疫抑制药物，可防止移植后器官排斥。该药物通过P-糖蛋白（ABCB1）从细胞中转运，并且是细胞色素P450（CYP）3A酶，特别是CYP3A4和CYP3A5的代谢底物。在编码CYP3A4、CYP3A5和ABCB1的基因中已鉴定出几种单核苷酸多态性（SNP），包括CYP3A4 - 392A/G（rs2740574）、CYP3A5 6986A/G（rs776746）和ABCB1 3435C/T（rs1045642）。本研究旨在评估墨西哥肾移植（KT）患者中CYP3A4 - 392A/G、CYP3A5 - 6986A/G和ABCB1 - 3435C/T多态性与他克莫司、血清浓度以及可能影响他克莫司药代动力学的生化参数之间的关联。
纳入46例接受不同组合他克莫司免疫抑制治疗的肾移植受者（KTR）。使用qPCR TaqMan对CYP3A4、CYP3A5和ABCB1基因多态性进行基因分型。评估血清他克莫司浓度（实测值）和干预变量。在基线和1个月后进行逻辑回归分析，以评估多态性、干预变量与他克莫司浓度之间的关联程度。
CYP3A5 - 6986 A/G多态性的GG基因型与他克莫司药代动力学变异性相关，在病程1个月时比值比（OR）为4.35（95%可信区间：1.13 - 21.9；P = 0.0458）；在多变量逻辑回归中，CYP3A5 - 6986GG基因型的OR为9.32（95%可信区间：1.54 - 93.08；P = 0.028），以及使用增加血清他克莫司浓度的药物或药剂的OR为9.52（95%可信区间：1.79 - 88.23；P = 0.018）与他克莫司药代动力学变异性密切相关。
这项针对墨西哥人群的研究结果表明，CYP3A5 - 6986 A/G GG基因型与他克莫司浓度超过15 ng/dL的可能性增加四倍相关。CYP3A5 - 6986GG基因型与增加他克莫司浓度的药物的共同出现与他克莫司水平高于15 ng/mL的风险增加九倍相关。因此，这些患者对他克莫司相关毒性的易感性增加。
