Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug...

Area of Science:

• Pharmacology
• Biochemistry
• Toxicology

Background:

• Species differences in renal drug transporters hinder accurate prediction of drug toxicity in preclinical models.
• Adefovir, an antiviral, demonstrated significant nephrotoxicity in humans, highlighting the need to understand species-specific transporter interactions.

Purpose of the Study:

• To investigate species differences in the interaction kinetics of acyclic nucleoside phosphonates (ANPs) with organic anion transporter 1 (OAT1).
• To identify specific amino acid residues responsible for these observed kinetic differences in OAT1.

Main Methods:

• Utilized OAT1 stably transfected human embryonic kidney 293 cells to assess tenofovir kinetics.
• Employed chimeric and site-directed mutagenesis studies, alongside comparative structure modeling, to pinpoint key amino acid residues.
• Compared OAT1 orthologs from various species, including humans, preclinical animals, and primates.

Main Results:

• Human OAT1 (hOAT1) exhibited a significantly lower K_m for tenofovir compared to OAT1 orthologs from cynomolgus monkey, mouse, rat, and dog.
• Serine at position 203 (S203) in hOAT1 was identified as the critical residue determining this lower K_m.
• S203 is conserved in apes, while alanine is conserved in preclinical species and Old World monkeys; higher transport efficiency was observed in OAT1 from apes with high serum uric acid levels.

Conclusions:

• A molecular mechanism for species-specific renal accumulation of nephrotoxic ANPs has been elucidated.
• The findings provide novel insights into OAT1 transport function and its evolutionary significance in primates.
• This research can improve the prediction of drug-induced nephrotoxicity across species.