title: Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA.
authors.forename: Yaofeng
authors.initials: Y
authors.lastname: Cheng
authors.forename: Arpine
authors.initials: A
authors.lastname: Vapurcuyan
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahidullah
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Pelis
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C491013:SLC22A2 protein, human; C490280:SLC22A7 protein, human; C053539:penciclovir; D006147:Guanine; D006152:Cyclic GMP; D015774:Ganciclovir; D000212:Acyclovir