Expression of drug transporters in human kidney: impact of sex, age, and ethnicity.

Stancy Joseph,Beverly Lyn-Cook,Bridgett Green-Knox,Tamara J Nicolson,Beverly Word,George Hammons

doi:10.1186/s13293-015-0020-3

Stancy Joseph, Beverly Lyn-Cook + Show 4 more

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https://doi.org/10.1186/s13293-015-0020-3

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Abstract

BackgroundDifferences in expression of drug transporters in human kidney contribute to changes in pharmacokinetics and toxicokinetics of a variety of drug compounds. The basal expression levels of genes involved in drug transport processes in the kidney introduces differences in bioavailability, distribution, and clearance of drugs, possibly influencing drug efficacy and adverse reactions. Sex differences in gene expression of transporters are a key cause of differences in sex-dependent pharmacokinetics, which may characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Therefore, evaluating the expression of drug transporters in normal human kidneys is important to better understand differences in drug bioavailability, distribution, and clearance of drugs in humans. Other factors such as age and ethnicity may also contribute to individual differences in gene expression of drug transporters in the human kidney.MethodsQuantitative real-time PCR (QRT-PCR) was performed to determine the gene expression of 30 drug transporters in 95 age-matched normal human kidney tissues. Multiple Student’s t-tests (Sidak-Bonferroni correction) and two-way ANOVA (Bonferroni correction) analyses were used to determine statistically significant differences.ResultsIn the 30 transporter genes examined, sex, ethnicity, and age differences in gene expression were exhibited in normal human kidney tissue. These changes in expression were not found to be differentially significant. However, sex-age and sex-ethnicity interactions were found to be statistically significant. For sex-age interactions, SCL22A12 was found to be significantly higher expressed in females <50 years compared to males <50 years. Expression levels of SLC22A2, SLC22A12, SLC6A16, and ABCB6 were significantly higher in females <50 years compared to females ≥50 years. In sex-ethnicity interactions, expression levels of ATP7B and KCNJ8 were found to be significantly higher in African American females compared to European American females. Also, the expression of SLC31A2 was significantly higher in European American males compared to European American females.ConclusionsSex, age, and ethnic differences impacted the expression of drug transporters in normal human kidneys, which suggests that the analysis of gene expression of drug transporters will aid in improving the usage/dosage of drug therapies influencing personalized medicine and susceptibility to adverse drug reactions.

Highlights

Differences in expression of drug transporters in human kidney contribute to changes in pharmacokinetics and toxicokinetics of a variety of drug compounds
The drug transporter genes selected for this study were detected in a previous Illumina Human Whole-Genome BeadChips (Human-6-v1; Illumina, San Diego, CA, USA) microarray-filtered analysis of age-matched human liver specimens that identified 1,640 genes differentially expressed according to sex [7]
Evaluation of the expression levels of the 27 drug transporter genes in females

Summary

Introduction

Differences in expression of drug transporters in human kidney contribute to changes in pharmacokinetics and toxicokinetics of a variety of drug compounds. The basal expression levels of genes involved in drug transport processes in the kidney introduces differences in bioavailability, distribution, and clearance of drugs, possibly influencing drug efficacy and adverse reactions. Evaluating the expression of drug transporters in normal human kidneys is important to better understand differences in drug bioavailability, distribution, and clearance of drugs in humans Other factors such as age and ethnicity may contribute to individual differences in gene expression of drug transporters in the human kidney. The variability of drug responses among individuals occurs because of complex and multifactorial contributions from genetic, environmental, disease/health, and drugdrug interactions [8] These factors alter drug absorption, metabolism, and pharmacokinetics in humans and lead to inter-individual variability of drug efficacy, safety, and adverse drug reactions [6,8]. Many factors influence the concentration of a drug in circulation or at the site of action and determine the resulting outcomes; one of these factors is the sex of the individual [9,10,11]

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