Secretion of N-(4-hydroxyphenyl) retinamide-retinol-binding protein from liver parenchymal cells: evidence for reduced affinity of the complex for transthyretin

Int J Cancer. 1997 May 16;71(4):654-9. doi: 10.1002/(sici)1097-0215(19970516)71:4<654::aid-ijc23>;2-a.


The synthetic retinoid 4-HPR has been shown to markedly lower the plasma concentration of both retinol and RBP in rats and humans. We have studied the effect of 4-HPR on the secretion of retinol-RBP from liver cells in vivo and in vitro. In rats maintained with a normal diet, a vitamin A-deficient diet or a normal diet supplemented with 4-HPR, chylomicrons [3H]retinyl esters were rapidly cleared from the plasma. The secretion of chylomicron-derived [3H]retinol from tissues to the circulation, however, was different. In control rats, the lymph-derived [3H]retinol peaked after about 2 hr, whereas 4-HPR treatment effectively reduced this peak of [3H]retinol. Our results suggest that 4-HPR inhibits secretion of retinol-RBP from the liver. Therefore, we decided to study the effect of 4-HPR on the secretion of RBP using the human hepatoma cell line HepG2. Retinol and 4-HPR were found to induce the secretion of RBP. The medium from cells treated with 4-HPR was immunoprecipitated with antibodies against human RBP. HPLC analysis of the precipitated RBP revealed the presence of 4-HPR. When the medium from cells incubated with either 4-HPR or retinol was applied to a TTR affinity column, we found that RBP from cells incubated with 4-HPR had a considerably reduced affinity for TTR. We conclude that 4-HPR binds RBP and thereby induces secretion of RBP in HepG2 cells, and that the secreted 4-HPR-RBP complex has a reduced affinity for TTR. This observation may explain the 4-HPR-induced reduction of plasma retinol and RBP observed in in vivo studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology
  • Chromatography, High Pressure Liquid
  • Chylomicrons / metabolism
  • Culture Media / chemistry
  • Diet
  • Fenretinide / pharmacokinetics*
  • Humans
  • Liver / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Prealbumin / metabolism*
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Retinol-Binding Proteins / metabolism*
  • Retinol-Binding Proteins, Plasma
  • Vitamin A Deficiency / metabolism


  • Chylomicrons
  • Culture Media
  • Prealbumin
  • Retinol-Binding Proteins
  • Retinol-Binding Proteins, Plasma
  • Fenretinide