Expression of CYP3A5 and P-glycoprotein in Renal Allografts With Histological Signs of Calcineurin Inhibitor Nephrotoxicity
- 27 May 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Transplantation
- Vol. 91 (10), 1098-1102
- https://doi.org/10.1097/tp.0b013e3182177502
Abstract
Background. Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1). Methods. We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21). In addition, we studied the association between renal expression and donor and recipient single-nucleotide polymorphisms CYP3A5 A6986G (rs776746), ABCB1 C3435T (rs1045642), and G2677T (rs2032582). Results. CYP3A5 positivity at the brushborder of the proximal tubules was present in 47% of CNIT and 14% of control biopsies (PPCYP3A5 A6986G and ABCB1 C3435T and G2677T in donors and recipients was not predictive of the renal expression profile of these molecules. Conclusions. Based on retrospectively collected data of 103 renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil and corticosteroids, we found that renal expression and localization of CYP3A5 but not P-gp is associated with the occurrence of CNIT. Common genetic polymorphisms in these proteins did not influence their expression profile as measured by immunohistochemistry.Keywords
This publication has 26 references indexed in Scilit:
- Tacrolimus Dose Requirements and CYP3A5 Genotype and the Development of Calcineurin Inhibitor-Associated Nephrotoxicity in Renal Allograft RecipientsTherapeutic Drug Monitoring, 2010
- Calcineurin Inhibitor NephrotoxicityClinical Journal of the American Society of Nephrology, 2009
- Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicityNephrology Dialysis Transplantation, 2007
- A "Silent" Polymorphism in the MDR 1 Gene Changes Substrate SpecificityScience, 2007
- Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine–sirolimus interactionKidney International, 2006
- The Natural History of Chronic Allograft NephropathyNew England Journal of Medicine, 2003
- CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adultsJournal of Applied Physiology, 2003
- Cytochrome P450 CYP3A in human renal cell cancerBritish Journal of Cancer, 1999
- HISTOPATHOLOGIC FINDINGS FROM 2-YEAR PROTOCOL BIOPSIES FROM A U.S. MULTICENTER KIDNEY TRANSPLANT TRIAL COMPARING TACROLIMUS VERSUS CYCLOSPORINETransplantation, 1998
- Cyclosporine-Associated Chronic NephropathyNew England Journal of Medicine, 1984