Reduced Hepatic Uptake and Intestinal Excretion of Organic Cations in Mice with a Targeted Disruption of the Organic Cation Transporter 1 (Oct1 [Slc22a1]) Gene

Abstract

The polyspecific organic cation transporter 1 (OCT1 [SLC22A1]) mediates facilitated transport of small (hydrophilic) organic cations. OCT1 is localized at the basolateral membrane of epithelial cells in the liver, kidney, and intestine and could therefore be involved in the elimination of endogenous amines and xenobiotics via these organs. To investigate the pharmacologic and physiologic role of this transport protein, we generated Oct1 knockout (Oct1 ؊/؊ ) mice. Oct1 ؊/؊ mice appeared to be viable, healthy, and fertile and displayed no obvious phenotypic abnormalities. The role of Oct1 in the pharmacology of substrate drugs was studied by comparing the distribution and excretion of the model substrate tetraethylammonium (TEA) after intravenous administration to wild-type and Oct1 ؊/؊ mice. In Oct1 ؊/؊ mice, accumulation of TEA in liver was four to sixfold lower than in wild-type mice, whereas direct intestinal excretion of TEA was reduced about twofold. Excretion of TEA into urine over 1 h was 53% of the dose in wild-type mice, compared to 80% in knockout mice, probably because in Oct1 ؊/؊ mice less TEA accumulates in the liver and thus more is available for rapid excretion by the kidney. In addition, we found that absence of Oct1 leads to decreased liver accumulation of the anticancer drug metaiodobenzylguanidine and the neurotoxin 1-methyl-4-phenylpyridium. In conclusion, our data show that Oct1 plays an important role in the uptake of organic cations into the liver and in their direct excretion into the lumen of the small intestine.The facilitated transport of organic cations, which include many clinically used drugs and endogenous compounds, is mediated by the family of organic cation transport proteins (OCT [SLC22A]). This family currently consists of five members: OCT1, OCT2, and OCT3 (6,7,21,23,33) and the more distantly related OCTN1 (26) and OCTN2 (34). The organic cation transporters are localized in the plasma membrane of epithelial cells and are characterized by a predicted 12-transmembrane-domain (TMD) structure and a large extracellular hydrophilic loop between TMD1 and TMD2 (reviewed in references 4 and 13). In rodents, Oct1 (Slc22a1) is highly expressed in the liver, kidney, and small intestine (7, 23), whereas in humans it is expressed primarily in the liver (6). In vitro, Oct1 mediates the facilitated diffusion of small, relatively hydrophilic cations, including the model compounds tetraethylammonium (TEA) and N 1 -methylnicotinamide, the neurotoxin 1-methyl-4-phenylpyridinium (MPP ϩ ), and also monoamine transmitters such as adrenaline and dopamine (1, 35). Larger, more hydrophobic cations like the antiarrhythmics quinine and quinidine are inhibitors of Oct1-mediated transport but are not transported by Oct1 (18). Oct2 has a substrate specificity similar to that of Oct1, but its expression is limited to the kidney and specific regions in the brain (8). The distribution of Oct1 and Oct2 in tissues has been studied by immunohistochemistry in the rat. Oct1 is localized at the sinusoidal (basola...

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

“…Thus, shortly after iv administration [ 14 C]TEA plasma levels, i.e., plasma drug availability, may be higher in BDL than in sham-operated rats resulting in an initially more rapid clearance of TEA from plasma via the kidney, which is the main excretory route for small organic cations in contrast to biliary excretion, 33 which contributes only minimally to the overall clearance of TEA. 19 However, because we did not analyze [ 14 C]TEA levels in plasma or urine at earlier time points, this possibility remains speculative.…”

“…These results are consistent with findings in Oct1 knockout mice where the hepatic accumulation of [ 14 C]TEA was only 23% of that in wild-type mice. 19 Because Oct1 is an electrogenic transporter, 2 changes in the membrane potential could theoretically also affect [ 14 C]TEA accumulation in the liver.…”

“…16 Recent studies in Oct1 knockout mice further suggest that Oct1 is the major if not the only physiologically significant hepatic uptake system for small organic cations. 19 Cholestatic liver injury results in the down-regulation of several basolateral membrane transport proteins, including sodium-dependent taurocholate cotransporting polypeptide (Ntcp, Slc10a1) and Oatp1 (Slc21a1). 20 -22 These alterations are regarded as adaptive responses to cholestasis that may serve to diminish the hepatic accumulation of toxic bile salts and other substances.…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…Thus, transporters appear to play important roles in the absorption, distribution and elimination of metformin. Many studies have shown that metformin is a substrate of various polyspecific organic cation transporters, which are important determinants of pharmacokinetics, including OCT1 (SLC22A1), OCT2 (SLC22A2), OCT3 (SLC22A3), MATE1 (SLC47A1), MATE2 (SLC47A2), PMAT (SLC29A4), and OCTN1 (SLC22A4) [11][12][13][14][15][16] (Fig. 1.1, Table 1).…”

OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin

“…Because of its multispecificity for many xenobiotics and its abundant expression in the liver, it has been proposed that the primary role of OCT1 is to work in concert with drug-metabolizing enzymes (e.g., cytochrome P450s) in detoxification pathways in the liver (5). In fact, with the exception of changes in hepatic drug disposition, Oct1 knockout mice appear healthy with no obvious phenotypic abnormalities (3,6).…”