The Antiviral Nucleotide Analogs Cidofovir and Adefovir Are Novel Substrates for Human and Rat Renal Organic Anion Transporter 1

Abstract

Nephrotoxicity is the dose-limiting clinical adverse effect of cidofovir and adefovir, two potent antiviral therapeutics. Because renal uptake likely plays a role in the etiology of cidofovir- and adefovir-associated nephrotoxicity, we attempted to identify a renal transporter capable of interacting with these therapeutics. A cDNA clone was isolated from a human renal library and designated human organic anion transporter 1 (hOAT1). Northern analysis detected a specific 2.5-kilobase pair hOAT1 transcript only in human kidney. However, reverse transcription-polymerase chain reaction revealed hOAT1 expression in human brain and skeletal muscle, as well. Immunoblot analysis of human kidney cortex demonstrated that hOAT1 is an 80- to 90-kilodalton heterogeneous protein modified by abundant N-glycosylation. Xenopus laevis oocytes expressing hOAT1 supported probenecid-sensitive uptake of [(3)H]p-aminohippurate (K(m) = 4 microM), which was trans-stimulated in oocytes preloaded with glutarate. Importantly, both hOAT1 and rat renal organic anion transporter 1 (rROAT1) mediated saturable, probenecid-sensitive uptake of cidofovir, adefovir, and other nucleoside phosphonate antivirals. The affinity of hOAT1 toward cidofovir and adefovir (K(m) = 46 and 30 microM, respectively) was 5- to 9-fold higher compared with rROAT1 (K(m) = 238 and 270 microM, respectively). These data indicate that hOAT1 may significantly contribute to the accumulation of cidofovir and adefovir in renal proximal tubules and, thus, play an active role in the mechanism of nephrotoxicity associated with these antiviral therapeutics.

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…This later proved to be true, but only in part, as several other transporters are now known to be involved. Soon after rOat1 had been cloned, other Oat1 orthologs were identified; in human, pig, rabbit, mouse, flounder and C. elegans [43][44][45][46][47][48][49][50][51]. To date, Oat1 message has been detected in kidney, choroid plexus and olfactory mucosa [52][53][54].…”

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

“…The basolateral exchanger for organic anions and dicarboxylates was cloned by three independent groups (5-7) in 1997 and named OAT1 (rat), ROAT1 (rat), or fROAT1 (winter flounder). The homologous protein was cloned from human kidney only recently and was called hOAT1 (8) or hPAHT (9,10). The genomic DNA from human hOAT1 is organized in ten exons, and up to now four isoforms are described (11).…”

Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

“…As toxins and cytotoxic drugs are taken up by OAT1 and OAT3, these toxic substances may exert toxic effects on the proximal tubule cells and cause renal injury. In vitro studies with OAT1-transfected cells showed that OAT1 over-expression sensitizes the cytotoxicity caused by antiviral drugs, adefovir and cidofovir [23]. Coadministration of the inhibitors of OATs may reduce the extent of OAT-induced nephrotoxicity [24].…”