TY - JOUR
T1 - Characterization of Human Organic Anion Transporter 4 (hOAT4) and Mouse Oat5 (mOat5) As Functional Orthologs for Renal Anion Uptake and Efflux Transport
AU - Martinez-Guerrero, Lucy J.
AU - Zhang, Xiaohong
AU - Wright, Stephen H.
AU - Cherrington, Nathan J.
N1 - Publisher Copyright:
© 2024 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2024/12/1
Y1 - 2024/12/1
N2 - Organic anions (OAs) are compounds including drugs or toxicants that are negatively charged at physiologic pH and are typically transported by organic anion transporters (OATs). Human OAT4 (SLC22A11) is expressed in the apical membrane of renal proximal tubules. Although there is no rodent ortholog of hOAT4, rodents express Oat5 (Slc22a19), an anion exchanger that is also localized to the apical membrane of renal proximal tubule cells. The purpose of this study was to determine the functional similarity between mouse Oat5 and human OAT4. Chinese hamster ovary (CHO) cells expressing SLC22A11 or Slc22a19 were used to assess the transport characteristics of radiolabeled ochratoxin (OTA). We determined the kinetics of OTA transport; the resulting Michaelis constant (Kt) and maximal rate of mediated substrate transport (Jmax) values were very similar for both hOAT4 and mOat5: Kt 3.9 and 7.2 lM, respectively, and Jmax 4.4 and 3.9 pmol/cm2, respectively. For the profile of OTA inhibition by OAs, IC50 values were determined for several clinically important drugs and toxicants. The resulting IC50 values ranged from 9 lM for indomethacin to ͂600 lM for the diuretic hydrochlorothiazide. We measured the efflux of OTA from preloaded cells; both hOAT4 and mOat5 supported the efflux of OTA. These data support the hypothesis that OAT4 and Oat5 are functional orthologs and share selectivity for OTA both for reabsorption and secretion.
AB - Organic anions (OAs) are compounds including drugs or toxicants that are negatively charged at physiologic pH and are typically transported by organic anion transporters (OATs). Human OAT4 (SLC22A11) is expressed in the apical membrane of renal proximal tubules. Although there is no rodent ortholog of hOAT4, rodents express Oat5 (Slc22a19), an anion exchanger that is also localized to the apical membrane of renal proximal tubule cells. The purpose of this study was to determine the functional similarity between mouse Oat5 and human OAT4. Chinese hamster ovary (CHO) cells expressing SLC22A11 or Slc22a19 were used to assess the transport characteristics of radiolabeled ochratoxin (OTA). We determined the kinetics of OTA transport; the resulting Michaelis constant (Kt) and maximal rate of mediated substrate transport (Jmax) values were very similar for both hOAT4 and mOat5: Kt 3.9 and 7.2 lM, respectively, and Jmax 4.4 and 3.9 pmol/cm2, respectively. For the profile of OTA inhibition by OAs, IC50 values were determined for several clinically important drugs and toxicants. The resulting IC50 values ranged from 9 lM for indomethacin to ͂600 lM for the diuretic hydrochlorothiazide. We measured the efflux of OTA from preloaded cells; both hOAT4 and mOat5 supported the efflux of OTA. These data support the hypothesis that OAT4 and Oat5 are functional orthologs and share selectivity for OTA both for reabsorption and secretion.
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U2 - 10.1124/jpet.123.001979
DO - 10.1124/jpet.123.001979
M3 - Article
C2 - 38627096
AN - SCOPUS:85210189974
SN - 0022-3565
VL - 391
SP - 378
EP - 386
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -