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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

Relative mRNA expression levels of drug transporters exhibiting ethnicity differences in human kidney tissue. The 30 transporter mRNA expressions for human kidney tissue were graphed to illustrated ethnic (European American and African American) differences. The bars represent the mean relative mRNA expression; the error bars indicate the standard error mean from n > 3 samples. Statistical analysis was performed using multiple Student’s t-test (Sidak-Bonferroni correction method (alpha = 5%)).
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Fig5: Relative mRNA expression levels of drug transporters exhibiting ethnicity differences in human kidney tissue. The 30 transporter mRNA expressions for human kidney tissue were graphed to illustrated ethnic (European American and African American) differences. The bars represent the mean relative mRNA expression; the error bars indicate the standard error mean from n > 3 samples. Statistical analysis was performed using multiple Student’s t-test (Sidak-Bonferroni correction method (alpha = 5%)).

Mentions: Differential expression by ethnic groups, European American and African American, was also evaluated. Twenty-two transporter genes (ABCA5, MRP1, MRP5, MXR, OST-Beta, KCNK5, ATP7B, TRPC4AP, SLC10A1, SLC6A16, SLC22A2, SLC22A12, SLC22A9, SLC25A13, SLC31A1, SLC31A2, SLC35F5, SLC43A1, SLC4A1AP, SLC5A10, SLC5A6, and SLC16A11) exhibited higher expression in European Americans compared to African Americans (Figure 5). In contrast, two transporter genes (ATP2B2 and SLC9A1) exhibited higher expression in African Americans compared to European Americans (Figure 5). And three transporter genes (ABCB1, ABCB6, and KCNJ8) were similarly expressed in European Americans and African Americans (Figure 5). This finding suggests ethnicity may also be a factor that contributes to differences in adverse responses in human kidney. Using multiple Student’s t-test (Sidak-Bonferroni correction method), statistical analyses were performed between the expression levels of European American and African Americans were found not to be significantly differentiated.Figure 5


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)

Relative mRNA expression levels of drug transporters exhibiting ethnicity differences in human kidney tissue. The 30 transporter mRNA expressions for human kidney tissue were graphed to illustrated ethnic (European American and African American) differences. The bars represent the mean relative mRNA expression; the error bars indicate the standard error mean from n > 3 samples. Statistical analysis was performed using multiple Student’s t-test (Sidak-Bonferroni correction method (alpha = 5%)).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Relative mRNA expression levels of drug transporters exhibiting ethnicity differences in human kidney tissue. The 30 transporter mRNA expressions for human kidney tissue were graphed to illustrated ethnic (European American and African American) differences. The bars represent the mean relative mRNA expression; the error bars indicate the standard error mean from n > 3 samples. Statistical analysis was performed using multiple Student’s t-test (Sidak-Bonferroni correction method (alpha = 5%)).
Mentions: Differential expression by ethnic groups, European American and African American, was also evaluated. Twenty-two transporter genes (ABCA5, MRP1, MRP5, MXR, OST-Beta, KCNK5, ATP7B, TRPC4AP, SLC10A1, SLC6A16, SLC22A2, SLC22A12, SLC22A9, SLC25A13, SLC31A1, SLC31A2, SLC35F5, SLC43A1, SLC4A1AP, SLC5A10, SLC5A6, and SLC16A11) exhibited higher expression in European Americans compared to African Americans (Figure 5). In contrast, two transporter genes (ATP2B2 and SLC9A1) exhibited higher expression in African Americans compared to European Americans (Figure 5). And three transporter genes (ABCB1, ABCB6, and KCNJ8) were similarly expressed in European Americans and African Americans (Figure 5). This finding suggests ethnicity may also be a factor that contributes to differences in adverse responses in human kidney. Using multiple Student’s t-test (Sidak-Bonferroni correction method), statistical analyses were performed between the expression levels of European American and African Americans were found not to be significantly differentiated.Figure 5

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