Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis.
During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of beta-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis.
Chen
Jiarong
J
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Terada
Tomohiro
T
Ogasawara
Ken
K
Katsura
Toshiya
T
Inui
Ken-ichi
K
D000220:Adaptation, Biological; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015310:Cefotiam / Q000493:pharmacokinetics; D002779:Cholestasis / Q000503:physiopathology*; D006801:Humans; D006932:Hyperbilirubinemia / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D051381:Rats
D001647:Bile Acids and Salts; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D015310:Cefotiam