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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro⁵⁸⁶

Discovery Drug Disposition and New Technology (E.Y.Z., Y.A.P., S.A.W., K.M.H.), Functional Genomics (D.-J.F., T.S.), and Diagnostics and Experimental Medicine (N.M.), Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana

The human proton-dependent dipeptide transporter (PEPT1, gene SLC15A1) is important for intestinal absorption of di- and tripeptides and a variety of peptidomimetic compounds. Using a DNA polymorphism discovery panel of 44 ethnically diverse individuals, nine nonsynonymous and four synonymous coding-region single-nucleotide polymorphisms (SNPs) were identified in PEPT1. HeLa cells were transiently transfected with plasmids constructed by site-directed mutagenesis for each of the nine nonsynonymous variants. Quantitative polymerase chain reaction showed that the mRNA transcription level of all of the mutants was comparable with the mRNA transcription level of the reference sequence in transfected HeLa cells. Functional analysis in transiently transfected HeLa cells revealed that all nonsynonymous variants retained similar pH-dependent activity and K_t values for [glycyl-1,2-¹⁴C]glycylsarcosine (Gly-Sar) uptake as the reference PEPT1. In addition, a group of seven peptide-like drugs showed inhibitory effect on Gly-Sar uptake by these variants comparable with the reference, suggesting conserved drug recognition. Of the nine nonsynonymous SNPs, a single SNP (P586L) demonstrated significantly reduced transport capacity as evidenced by a much lower V_max value. This was consistent with lower immunoactive protein level (Western analysis) and lower plasma membrane expression (immunocytochemical analysis). Therefore, Pro⁵⁸⁶ may have profound effect on PEPT1 translation, degradation, and/or membrane insertion.

Address correspondence to: Dr. Kathleen M. Hillgren, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: kathleen_m_hillgren{at}lilly.com

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