CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

N. Chandel¹, M. Minz², V. Jha^3
1Nephrology, PGIMER, Chandigarh/INDIA, ²Renal Tx Surgery, POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, Chandigarh/INDIA, ³Nephrology, POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, Chandigarh/INDIA

Body: Introduction: CYP3A4 and CYP3A5 are the main components of the cytochrome P450 enzyme system, responsible for metabolism of several drugs including calcineurin inhibitors (CNI). MDR1 gene, through its product P-glycoprotein (P-gp) is responsible for cellular efflux of CNIs. SNPs in these genes influence CNI levels and/or activity. We investigated the impact of SNPs on the transcription and function of these proteins. Methods: Genomic DNA was screened for five variants of reported functional relevance in CYP3A (CYP3A4*1B and CYP3A5*3) and MDR1 (C1236T and A2677T and C3435T) genes. RNA quantification was done in 40 subjects using real time PCR and results given in copy no /n mole (median). CYP and P-gp function was studied in 25 individuals selected on the basis of genotypes by 14-C labeled erythromycin breath (CYP) and urine (P-gp) tests. Subjects were administered 14-C labeled erythromycin and serial urine and breath samples were analyzed for radioactivity. Tacrolimus levels were measured using Abbot IMxII method. Results: CYP3A4AG (647.0 V AA74.70) and CYP3A5 AA (191.0 V GG88.35) genotype showed higher transcriptional activity (p<0.0001 and p=0.01 respectively). In the MDR1 gene, individuals with TT genotype at 1236(TT376 V CC2565.0) and 2677(TT 68.01 V GG 77095.0) positions and TTT (459.21 V CGC 1450.0) haplotype showed reduced transcript levels (p=0.02, 0.002 & 0.03 respectively). The transcript levels correlated significantly with the CP3A and P-gp activities. By the breath and urine tests, the CYP activity was found to be higher in subjects with CYP3A4AA(86.4±16.4) and CYP3A5 AA(120.1±50.4) genotypes whereas the MDR-CGC(11.9±2.9 V TTT 28.8±4.1) haplotype showed significantly higher Pgp activity with lower CPM p<0.001). Tacrolimus trough levels were significantly higher in individuals with CYP3A5 GG genotype (AA 53.0±23.1 V GG 80.9±33.2 (p<0.0001), corresponding to a lower enzyme activity.Conclusion: Variations in CP3A4, CYP3A5 and MDR1 genes have an impact on the activity of CYP and P-gp by significantly affecting gene transcription. These variations are likely to have asignificant impact on CNI metabolism.

Disclosure: All authors have declared no conflicts of interest.