Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs

Yaofeng Cheng, Arpine Vapurcuyan, Mohammad Shahidullah, Lauren M. Aleksunes, Ryan M. Pelis

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The organic anion transporters 1 and 3 (OAT1 and OAT3) and organic cation transporter 2 (OCT2) are important for renal tubular drug secretion. In contrast, evidence for OAT2 expression in the human kidney is limited, and its role in renal drug transport is unknown. Both mRNA (real-time polymerase chain reaction) and protein (Western blotting) for OAT2 were detected in renal cortex from eight donors, and interindividual variability in protein levels was 3-fold. OAT2 protein in the renal cortex was localized (by immunohistochemistry) to the basolateral domain of tubules, as were OAT1 and OAT3. The absolute abundance of OAT2 mRNA was similar to that of OAT1 mRNA and 3-fold higher than that of OCT2 mRNA but 10-fold lower than that of OAT3 mRNA. A previous observation that OAT2 transports cGMP led us to examine whether acyclovir, ganciclovir, and penciclovir are OAT2 substrates; they are guanine-containing antivirals that undergo active tubular secretion. Transport of the antivirals into human embryonic kidney cells was stimulated 10- to 20-fold by expression of OAT2, but there was little to no transport of the antivirals by OAT1, OAT3, or OCT2. The K m values for acyclovir, ganciclovir, and penciclovir transport were 94, 264, and 277 μM, respectively, and transport efficiencies were relatively high (6-24 μl·min -1·mg protein -1). This study provides definitive evidence for the expression of OAT2 in the human kidney and is the first to demonstrate that OAT2, compared with OAT1, OAT3, or OCT2, has a preference for antiviral drugs mainly eliminated in the urine via active secretion.

Original languageEnglish (US)
Pages (from-to)617-624
Number of pages8
JournalDrug Metabolism and Disposition
Volume40
Issue number3
DOIs
StatePublished - Mar 1 2012

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Organic Anion Transporters
Guanine
Antiviral Agents
Kidney
Cations
Messenger RNA
Ganciclovir
Acyclovir
Proteins
Pharmaceutical Preparations
Real-Time Polymerase Chain Reaction
Western Blotting
Immunohistochemistry
Observation
Urine

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

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abstract = "The organic anion transporters 1 and 3 (OAT1 and OAT3) and organic cation transporter 2 (OCT2) are important for renal tubular drug secretion. In contrast, evidence for OAT2 expression in the human kidney is limited, and its role in renal drug transport is unknown. Both mRNA (real-time polymerase chain reaction) and protein (Western blotting) for OAT2 were detected in renal cortex from eight donors, and interindividual variability in protein levels was 3-fold. OAT2 protein in the renal cortex was localized (by immunohistochemistry) to the basolateral domain of tubules, as were OAT1 and OAT3. The absolute abundance of OAT2 mRNA was similar to that of OAT1 mRNA and 3-fold higher than that of OCT2 mRNA but 10-fold lower than that of OAT3 mRNA. A previous observation that OAT2 transports cGMP led us to examine whether acyclovir, ganciclovir, and penciclovir are OAT2 substrates; they are guanine-containing antivirals that undergo active tubular secretion. Transport of the antivirals into human embryonic kidney cells was stimulated 10- to 20-fold by expression of OAT2, but there was little to no transport of the antivirals by OAT1, OAT3, or OCT2. The K m values for acyclovir, ganciclovir, and penciclovir transport were 94, 264, and 277 μM, respectively, and transport efficiencies were relatively high (6-24 μl·min -1·mg protein -1). This study provides definitive evidence for the expression of OAT2 in the human kidney and is the first to demonstrate that OAT2, compared with OAT1, OAT3, or OCT2, has a preference for antiviral drugs mainly eliminated in the urine via active secretion.",
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Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. / Cheng, Yaofeng; Vapurcuyan, Arpine; Shahidullah, Mohammad; Aleksunes, Lauren M.; Pelis, Ryan M.

In: Drug Metabolism and Disposition, Vol. 40, No. 3, 01.03.2012, p. 617-624.

Research output: Contribution to journalArticle

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