CYP3A5 Genotype-Phenotype Analysis in the Human Kidney Reveals a Strong Site-Specific Expression of CYP3A5 in the Proximal Tubule in Carriers of the CYP3A5*1 Allele
Open Access
- 3 January 2012
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 40 (4), 639-641
- https://doi.org/10.1124/dmd.111.042648
Abstract
Interindividual variability in the drug-metabolizing activity of the CYP3A5 enzyme is mainly due to a single nucleotide polymorphism in CYP3A5, leading to low expression in homozygous CYP3A5*3/*3 individuals compared with CYP3A5*1 allele carriers. In the human kidney, expression of CYP3A5 has been implicated in blood pressure regulation and calcineurin inhibitor-associated nephrotoxicity. The effect of the CYP3A5*1/*3 polymorphism on the expression level and protein distribution within the human kidney is not well characterized. Therefore, we performed a genotype-phenotype analysis of CYP3A5 mRNA and protein expression in the human kidney. To this end, we analyzed sections of normal kidney tissue obtained from 93 white individuals undergoing nephrectomy by quantitative mRNA expression analysis. Qualitative protein expression analysis of CYP3A5 was performed by immunohistochemistry. Mean renal mRNA expression of carriers of the CYP3A5*1 (n = 12) allele was more than 18-fold higher than that of CYP3A5*3/*3 carriers (n = 81, p < 0.001). Immunohistochemical analysis demonstrated CYP3A5 protein in all epithelia of the nephron in kidney sections with the CYP3A5*3/*3 genotype. In carriers of the CYP3A5*1 allele, a strong increase in protein expression of CYP3A5 was detected, and this was confined to the proximal tubule. This study confirms a significant effect of the CYP3A5*1/*3 polymorphism on CYP3A5 expression in the normal human kidney and reveals a strong nephron segment-specific difference in the CYP3A5 protein expression limited to the proximal tubule.Keywords
This publication has 22 references indexed in Scilit:
- Expression of CYP3A5 and P-glycoprotein in Renal Allografts With Histological Signs of Calcineurin Inhibitor NephrotoxicityTransplantation, 2011
- Tacrolimus Dose Requirements and CYP3A5 Genotype and the Development of Calcineurin Inhibitor-Associated Nephrotoxicity in Renal Allograft RecipientsTherapeutic Drug Monitoring, 2010
- CYP3A5 polymorphism and sensitivity of blood pressure to dietary salt in Japanese menJournal of Human Hypertension, 2009
- CYP3A5 and ABCB1 genes and hypertensionPharmacogenomics, 2009
- Comparative expression analysis of the renin–angiotensin system components between white and brown perivascular adipose tissueJournal of Endocrinology, 2008
- CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by SaltHypertension, 2007
- No association of the CYP3A5*1 allele with blood pressure and left ventricular mass and geometry: the KORA/MONICA Augsburg echocardiographic substudyClinical Science, 2006
- Association of CYP3A5 genotypes with blood pressure and renal function in African familiesJournal Of Hypertension, 2006
- Association Between the CYP3A5 Genotype and Blood PressureHypertension, 2005
- The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patientsPharmacogenetics, 2004