• Journal of Pharmaceutical Investigation
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• v.36 no.4
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• pp.283-286
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• 2006

The present study aimed to investigate the interaction of nucleoside analogs with human organic anion transporter 1 and 3(hOAT1 and hOAT3) that play a primary role in the tubular uptake of endogenous and exogenous organic anions in the kidney. The interactions of ddC, ara-C, ara-A and ara-U with hOAT1 and hOAT3 were examined using MDCK cells stably overexpressing hOAT1 or hOAT3. Among the tested drugs, ddC showed the highest affinity to hOAT1 with $IC_{50}$ values of 5.2 mM, while ara-A, ara-C and ara-U weakly inhibited the cellular uptake of $[^3H]-PAH$ in MDCK-hOAT1 cells at 1 mM. In contrast, all the tested drugs did not have any inhibition effect on the cellular uptake of $[^3H]-estrone$ sulfate in MDCK-hOAT3 cells over the drug concentration of 0.01-2 mM, implying that they might not interact with hOAT3. Taken all together, the present study suggests that hOAT1 could weakly interact with nucleoside analogues such as ddC, ara-C, ara-A and ara-U but the interaction with hOAT3 during the urinary excretion of these nucleoside analogues may be negligible in the kidney.

• Molecules and Cells
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• v.25 no.2
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• pp.265-271
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• 2008

Single nucleotide polymorphisms (SNPs) are the most common form of human genetic variation. Non-synonymous SNPs (nsSNPs) change an amino acid. Organic anion transporters (OATs) play an important role in eliminating or reabsorbing endogenous and exogenous organic anionic compounds. Among OATs, hOAT4 mediates high affinity transport of estrone sulfate and dehydroepiandrosterone sulfate. The rapid bone loss that occurs in post-menopausal women is mainly due to a net decrease of estrogen. In the present study we searched for SNPs within the exon regions of hOAT4 in Korean women osteoporosis patients. Fifty healthy subjects and 50 subjects with osteoporosis were screened for genetic polymorphism in the coding region of SLC22A11 (hOAT4) using GC-clamp PCR and denaturing gradient gel electrophoresis (DGGE). We found three SNPs in the hOAT4 gene. Two were in the osteoporosis group (C483A and G832A) and one in the normal group (C847T). One of the SNPs, G832A, is an nsSNP that changes the $278^{th}$ amino acid from glutamic acid to lysine (E278K). Uptake of [$3^H$] estrone sulfate by oocytes injected with the hOAT4 E278K mutant was reduced compared with wild-type hOAT4. Km values for wild type and E278K were $0.7{\mu}M$ and $1.2{\mu}M$, and Vmax values were 1.8 and 0.47 pmol/oocyte/h, respectively. The present study demonstrates that hOAT4 variants can causing inter-individual variation in anionic drug uptake and, therefore, could be used as markers for certain diseases including osteoporosis.