RT Journal Article
SR Electronic
T1 The Antiviral Nucleotide Analogs Cidofovir and Adefovir Are Novel Substrates for Human and Rat Renal Organic Anion Transporter 1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 570
OP 580
DO 10.1124/mol.56.3.570
VO 56
IS 3
A1 Tomas Cihlar
A1 Deborah C. Lin
A1 John B. Pritchard
A1 Michael D. Fuller
A1 Dirk B. Mendel
A1 Douglas H. Sweet
YR 1999
UL http://molpharm.aspetjournals.org/content/56/3/570.abstract
AB 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 abundantN-glycosylation. Xenopus laevis oocytes expressing hOAT1 supported probenecid-sensitive uptake of [3H]p-aminohippurate (K m = 4 μM), which wastrans-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 μM, respectively) was 5- to 9-fold higher compared with rROAT1 (K m = 238 and 270 μM, 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.