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.
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.
Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. juliane.bolbrinker@charite.de
Juliane
J
Bolbrinker
Stefanie
S
Seeberg
Martin
M
Schostak
Carsten
C
Kempkensteffen
Hans
H
Baelde
Emile
E
de Heer
Reinhold
R
Kreutz
D000483:Alleles; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D060888:Real-Time Polymerase Chain Reaction
C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A