Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations.
The polyspecific organic cation transporters 1 and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1(-/-) mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2(-/-) and Oct1/2(-/-) mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2(-/-) mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2(-/-) mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.
Jonker
Johan W
JW
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Wagenaar
Els
E
Van Eijl
Sven
S
Schinkel
Alfred H
AH
D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism; D002412:Cations / Q000378:metabolism*; D018390:Gene Targeting; D005919:Glomerular Filtration Rate; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism; D019789:Tetraethylammonium / Q000378:metabolism
D002250:Carbon Radioisotopes; D002412:Cations; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds; C491012:Slc22a2 protein, mouse; D019789:Tetraethylammonium; D007444:Inulin