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

Joseph S, Nicolson TJ, Hammons G, Word B, Green-Knox B, Lyn-Cook B - Biol Sex Differ (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Building 50, Room 630, HFT 100, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

Background: 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. 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.

Methods: Quantitative 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.

Results: In 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.

Conclusions: Sex, 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.

No MeSH data available.


Related in: MedlinePlus

Comparison of expression level for housekeeping gene, GAPDH, based on sex, age, and ethnicity. Box-whisker plot demonstrates cycle threshold (Ct) values from lower to upper quartiles intersected by median for (A) sex, (B) age, (C) ethnicity, (D) sex-age interaction, and (E) sex-ethnicity interaction. Statistical analysis for sex, age, and ethnicity was performed using non-parametric Mann–Whitney test. Statistical analysis for sex-age and sex-ethnicity interaction was performed using non-parametric Kruskal-Wallis test (see Table 3).
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Fig1: Comparison of expression level for housekeeping gene, GAPDH, based on sex, age, and ethnicity. Box-whisker plot demonstrates cycle threshold (Ct) values from lower to upper quartiles intersected by median for (A) sex, (B) age, (C) ethnicity, (D) sex-age interaction, and (E) sex-ethnicity interaction. Statistical analysis for sex, age, and ethnicity was performed using non-parametric Mann–Whitney test. Statistical analysis for sex-age and sex-ethnicity interaction was performed using non-parametric Kruskal-Wallis test (see Table 3).

Mentions: 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]. Twenty-six of these genes were utilized to determine which genes were also differentially expressed in human kidney tissues. Four additional transporter genes, which were previously noted as being differentially expressed in the liver, MXR, MRP5, MRP1, and ABCB1, were also examined [22]. As part of mRNA expression analyses, an appropriate choice of housekeeping gene(s) is critical. To confirm the utilization of a single housekeeping gene, GAPDH, we averaged the GAPDH cycle threshold (Ct) value of the 95 human kidney samples as well as compared the average GAPDH Ct values based on sex, age, and ethnicity. The average the GAPDH Ct value (mean ± SEM) of the 95 human kidney samples was 30.47 ± 0.36. As shown in Figure 1, there was no significant difference in average GAPDH Ct values (mean ± SEM) based on sex (female: 29.94 ± 0.53 and male: 30.77 ± 0.48; Figure 1A), age (age < 50 years: 31.00 ± 0.71 and age ≥ 50 years: 30.32 ± 0.42; Figure 1B), and ethnicity (African American: 29.91 ± 0.65 and European American: 30.65 ± 0.45; Figure 1C). Further analysis showed no significant difference of GAPDH Ct values based on sex-age (Figure 1D, Table 3) and sex-ethnicity (Figure 1E, Table 3) interactions. Based on these findings, the use of a single reference gene, GAPDH, is acceptable and the observed change in regulation is reflective of the target gene not the reference gene.Figure 1


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

Joseph S, Nicolson TJ, Hammons G, Word B, Green-Knox B, Lyn-Cook B - Biol Sex Differ (2015)

Comparison of expression level for housekeeping gene, GAPDH, based on sex, age, and ethnicity. Box-whisker plot demonstrates cycle threshold (Ct) values from lower to upper quartiles intersected by median for (A) sex, (B) age, (C) ethnicity, (D) sex-age interaction, and (E) sex-ethnicity interaction. Statistical analysis for sex, age, and ethnicity was performed using non-parametric Mann–Whitney test. Statistical analysis for sex-age and sex-ethnicity interaction was performed using non-parametric Kruskal-Wallis test (see Table 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352278&req=5

Fig1: Comparison of expression level for housekeeping gene, GAPDH, based on sex, age, and ethnicity. Box-whisker plot demonstrates cycle threshold (Ct) values from lower to upper quartiles intersected by median for (A) sex, (B) age, (C) ethnicity, (D) sex-age interaction, and (E) sex-ethnicity interaction. Statistical analysis for sex, age, and ethnicity was performed using non-parametric Mann–Whitney test. Statistical analysis for sex-age and sex-ethnicity interaction was performed using non-parametric Kruskal-Wallis test (see Table 3).
Mentions: 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]. Twenty-six of these genes were utilized to determine which genes were also differentially expressed in human kidney tissues. Four additional transporter genes, which were previously noted as being differentially expressed in the liver, MXR, MRP5, MRP1, and ABCB1, were also examined [22]. As part of mRNA expression analyses, an appropriate choice of housekeeping gene(s) is critical. To confirm the utilization of a single housekeeping gene, GAPDH, we averaged the GAPDH cycle threshold (Ct) value of the 95 human kidney samples as well as compared the average GAPDH Ct values based on sex, age, and ethnicity. The average the GAPDH Ct value (mean ± SEM) of the 95 human kidney samples was 30.47 ± 0.36. As shown in Figure 1, there was no significant difference in average GAPDH Ct values (mean ± SEM) based on sex (female: 29.94 ± 0.53 and male: 30.77 ± 0.48; Figure 1A), age (age < 50 years: 31.00 ± 0.71 and age ≥ 50 years: 30.32 ± 0.42; Figure 1B), and ethnicity (African American: 29.91 ± 0.65 and European American: 30.65 ± 0.45; Figure 1C). Further analysis showed no significant difference of GAPDH Ct values based on sex-age (Figure 1D, Table 3) and sex-ethnicity (Figure 1E, Table 3) interactions. Based on these findings, the use of a single reference gene, GAPDH, is acceptable and the observed change in regulation is reflective of the target gene not the reference gene.Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Building 50, Room 630, HFT 100, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

Background: 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. 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.

Methods: Quantitative 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.

Results: In 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.

Conclusions: Sex, 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.

No MeSH data available.


Related in: MedlinePlus