RT Journal Article
SR Electronic
T1 Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.111153
DO 10.1124/mol.117.111153
A1 Ling Zou
A1 Adrian Stecula
A1 Anshul Gupta
A1 Bhagwat Prasad
A1 Huan-Chieh Chien
A1 Sook Wah Yee
A1 Li Wang
A1 Jashvant D Unadkat
A1 Simone H Stahl
A1 Katherine S Fenner
A1 Kathleen M Giacomini
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/05/02/mol.117.111153.abstract
AB 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 HIV due to pronounced nephrontoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of antiviral drugs with OAT1 (SLC22A6) and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected HEK293 cells, the Km of tenofovir for human OAT1 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. Further, 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 levels than 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 antiviral drugs and a novel insight into OAT1 transport function in primate evolution.