Title: CYP3A5 Genotype-Phenotype Analysis in the Human Kidney Reveals a Strong Site-Specific Expression of CYP3A5 in the Proximal Tubule in Carriers of the <i>CYP3A5</i>*<i>1</i> Allele
Abstract: Interindividual variability in the drug-metabolizing activity of the CYP3A5 enzyme is mainly due to a single nucleotide polymorphism in <i>CYP3A5</i>, leading to low expression in homozygous <i>CYP3A5</i>*<i>3</i>/*<i>3</i> individuals compared with <i>CYP3A5</i>*<i>1</i> 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 <i>CYP3A5</i>*<i>1</i>/*<i>3</i> 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 <i>CYP3A5</i>*<i>1</i> (<i>n</i> = 12) allele was more than 18-fold higher than that of <i>CYP3A5</i>*<i>3</i>/*<i>3</i> carriers (<i>n</i> = 81, <i>p</i> < 0.001). Immunohistochemical analysis demonstrated CYP3A5 protein in all epithelia of the nephron in kidney sections with the <i>CYP3A5</i>*<i>3</i>/*<i>3</i> genotype. In carriers of the <i>CYP3A5</i>*<i>1</i> 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 <i>CYP3A5</i>*<i>1</i>/*<i>3</i> 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.
Publication Year: 2012
Publication Date: 2012-01-03
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 24
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