TY - JOUR T1 - Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 689 LP - 699 DO - 10.1124/mol.117.111153 VL - 94 IS - 1 AU - Ling Zou AU - Adrian Stecula AU - Anshul Gupta AU - Bhagwat Prasad AU - Huan-Chieh Chien AU - Sook Wah Yee AU - Li Wang AU - Jashvant D. Unadkat AU - Simone H. Stahl AU - Katherine S. Fenner AU - Kathleen M. Giacomini Y1 - 2018/07/01 UR - http://molpharm.aspetjournals.org/content/94/1/689.abstract N2 - Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the Km value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower Km value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution. ER -