Characterization of the hepatic cellular uptake of α 1-acid glycoprotein (AGP), part 1: A peptide moiety of human AGP is recognized by the hemoglobin β-chain on mouse liver parenchymal cells

Koji Nishi, Hisakazu Komori, Mari Kikuchi, Nao Uehara, Naoko Fukunaga, Kazuaki Matsumoto, Hiroshi Watanabe, Keisuke Nakajou, Shogo Misumi, Ayaka Suenaga, Toru Maruyama, Masaki Otagiri

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Abstract

Human α 1-acid glycoprotein (AGP), a serum glycoprotein, is known to have anti-inflammatory activity. We recently reported that AGP was mainly incorporated into the liver in mice via a receptor-mediated pathway, although the mechanism for this was largely unknown. The objective of this study was to identify the specific cellular surface protein that recognizes the peptide moiety of AGP. Pharmacokinetic studies of 111In-AGP and 111In -recombinant glycan-deficient AGP (rAGP) in mice demonstrated that both AGPs are mainly distributed to the liver and kidney, but hepatic and renal uptake clearance of rAGP was higher than that for AGP. Hepatic uptake of rAGP was inhibited in the presence of 100-fold excess of unlabeled AGP, indicating that the hepatic uptake of rAGP shared a common route with that of AGP and that it recognized the peptide moiety of AGPs. In ligand blotting analyses using crude cellular membrane fraction of mice liver, a band corresponding to a 16 kDa protein was observed to bind to both AGPs. Interestingly, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry MALDI-TOF-MS and western blotting analyses indicated that this 16 kDa protein is the hemoglobin β-chain (HBB). It, therefore, appears that HBB is associated with the hepatic uptake of AGP via a direct interaction with its peptide moiety.

Original languageEnglish
Pages (from-to)1599-1606
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume101
Issue number4
DOIs
Publication statusPublished - 2012 Apr
Externally publishedYes

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Keywords

  • Alpha 1-acid glycoprotein
  • Distribution
  • Glycoproteins/glycoprotein receptors
  • Hepatic transport
  • Kinetics
  • Protein binding

ASJC Scopus subject areas

  • Pharmaceutical Science

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