Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicity.
BACKGROUND
Nephrotoxicity secondary to calcineurin inhibitors is common in renal transplant recipients, occurring in 76-94% of patients. The role of drug transporters (P-glycoprotein) and drug metabolizing enzymes (cytochrome P450) as predisposing factors toward nephrotoxicity or its prevention has not been thoroughly examined.


METHODS
The objective of this study was to analyse cytochrome P450 3A5 (CYP3A5) expression in kidneys of solid organ recipients by immunohistochemistry to determine if there is an association between expression of this enzyme and calcineurin inhibitor toxicity. Transplant recipients were compared with a control group.


RESULTS
Apical tubular plasma membrane staining for CYP3A5 was present in 62% of study and 100% of control biopsies (P=0.0012). Proximal and distal tubular nuclear staining intensity was similar between groups. Cytoplasmic staining in both the proximal (2.1+/-0.9 vs 1.4+/-0.9) and distal (2.8+/-0.5 vs 1.8+/-1.1) tubules was greater in the control vs study population specimens, respectively (P=0.0093 and P=0.0005, respectively). Regression models that controlled for use of CYP3A inhibiting and inducing medications, age, gender, race and glomerular filtration rate did not predict differences between study groups with regard to staining locations and intensity, except for the cytoplasm of the distal tubule, where intensity of staining was significantly lower in the study group (0.9+/-0.3; P=0.002).


CONCLUSIONS
This study showed decreased expression of CYP3A5 in nephrotoxic biopsies as compared with a control group. Our data suggest that the relationship between reduced presence of CYP3A5 in the kidney tubules and nephrotoxicity should be further explored to elucidate the role of this enzyme in mediating toxicity.
Joy
Melanie S
MS
Division of Nephrology and Hypertension, University of North Carolina School of Medicine, UNC Kidney Center, CB 7155, 7005 Burnett Womack Building, Chapel Hill, NC 27599-7155, USA. melanie_joy@med.unc.edu
Hogan
Susan L
SL
Thompson
Bawana D
BD
Finn
William F
WF
Nickeleit
Volker
V
D000328:Adult; D065095:Calcineurin Inhibitors; D002462:Cell Membrane / Q000201:enzymology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000201:enzymology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology*; D007686:Kidney Tubules, Distal / Q000201:enzymology; D007687:Kidney Tubules, Proximal / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D013194:Staining and Labeling
D065095:Calcineurin Inhibitors; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A