Phenolsulfonphthalein as a surrogate substrate to assess altered function of the prostaglandin transporter SLCO2A1

The prostaglandin (PG) transporter SLCO2A1 regulates PGE₂ signaling and interacts with many drugs, and SLCO2A1 defects is associated with PG metabolic disorders. This study aimed to characterize a non-metabolic phenolsulfonphthalein (PSP) transport mediated by SLCO2A1. PSP uptake by HEK293 cells expressing human SLCO2A1 (HEK/2A1 cells) was pH-independent and saturable with a K_m value of 54.5 ± 9.5 μM PGE₂ competitively inhibited PSP uptake with a K_i of 257.3 ± 22.8 nM. When PSP was intravenously (i.v.) injected, concentration-time curve showed a biphasic response. In Slco2a1-deficient (-/-) mice, AUC_inf tented to decrease and the central distribution volume (V₁) significantly increased, compared to wild-type (wt) counterparts. Intriguingly, Slco2a1-deficiency significantly reduced a ratio of tissue-to-plasma concentration in the lungs at 15 min after i.v. injection, suggesting that SLCO2A1 limits tissue distribution of PSP. In conclusion, these results prove that PSP is a potential surrogate for monitoring SLCO2A1 function, providing a new concept for diagnostics for the genetic diseases caused by defects in SLCO2A1 gene.