The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein
✍ Scribed by Dr. K. Sandy Pang; Pi Jun Wang; Alfred Y. Chung; Allan W. Wolkoff
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 96 KB
- Volume
- 28
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Oatp1, the organic anion transport polypeptide, is an integral membrane protein cloned from rat liver that mediates the uptake of various organic anions such as bromosulfophthalein (BSP) and taurocholate (TCA). Recent studies by others revealed that the thrombin inhibitor, CRC 220, a modified dipeptide, was transported by oatp1. The present study was designed to examine whether another modified peptide, enalapril, an angiotensin-converting enzyme inhibitor, was also a substrate. Transport was studied with enalapril (1 to 800 mol/L, with [ 3 H]enalapril) in a HeLa cell line stably transfected with oatp1-cDNA under the regulation of a Zn 2؉ -inducible promoter. Noninduced transfected cells (without zinc) that did not express oatp1 failed to take up enalapril. In contrast, cells expressing oatp1 transported enalapril, estrone sulfate (E 1 S), taurolithocholic acid sulfate (TLCAS), and the glutathione conjugate of BSP (BSPGSH). Uptake of enalapril by oatp1 at 37ЊC was substantially higher than that at 4ЊC. The rate at 37ЊC (uptake rates for induced -noninduced, transfected cells) was linear over 5 minutes and was concentration-dependent, characterized by a K m of 214 ؎ 67 mol/L and a V max of 0.51 ؎ 0.15 nmol/min/mg protein. Enalapril uptake was inhibited competitively by BSP (at 1, 5, 10, and 50 mol/L) and TCA (at 5, 25, and 100 mol/L) with inhibition constants (K i ) of 2 and 32 mol/L, respectively. The metabolite enalaprilat was, however, not transported by oatp1. That oatp1 is not a general transporter of anionic compounds was further shown by the lack of transport of harmol sulfate, benzoate, and hippurate. These observations attest to the role of oatp1 as a specific transporter for at least two classes of pharmacologically important pep-