PMID- 15454227
OWN - NLM
STAT- MEDLINE
DCOM- 20050505
LR  - 20131121
IS  - 0960-894X (Print)
IS  - 0960-894X (Linking)
VI  - 14
IP  - 21
DP  - 2004 Nov 1
TI  - In vitro plasma protein binding and aqueous aggregation behavior of astaxanthin 
      dilysinate tetrahydrochloride.
PG  - 5357-66
AB  - The tetrahydrochloride salt of astaxanthin di-L-lysinate (lys(2)AST) is a highly 
      water-dispersible astaxanthin-amino acid conjugate, with an aqueous 
      dispersibility of > or = 181.6 mg/mL. The statistical mixture of stereoisomers 
      has been well characterized as an aqueous-phase superoxide anion scavenger, 
      effective at micromolar (microM) concentrations. In the current study, the 
      aqueous aggregation behavior and in vitro plasma protein binding [with 
      fatty-acid-free human serum albumin (HSA) and alpha(1)-acid glycoprotein (AGP)] 
      were investigated with a suite of techniques, including circular dichroism (CD) 
      and UV-vis spectroscopy, ultrafiltration, competitive ligand displacement, and 
      fluorescence quenching. Induced CD bands obtained in Ringer buffer solution of 
      HSA demonstrated high affinity monomeric binding of the compound at low ligand 
      per protein (L/P) ratios (in aqueous solution alone the carotenoid molecules 
      formed card-pack aggregates). The binding constant ( approximately 10(6)M(-1)) 
      and the binding stoichiometry (approximately 0.2 per albumin molecule) were 
      calculated from CD titration data. CD displacement and ultrafiltration 
      experiments performed with marker ligands of HSA indicated that the ligand 
      binding occurred at a site distinct from the main drug binding sites of HSA 
      (i.e., Sites I and II). At intermediate L/P ratios, both monomeric and aggregated 
      ("chirally complexed") binding occurred simultaneously at distinct sites of the 
      protein. At high L/P ratios, chiral complexation predominantly occurred on the 
      asymmetric protein template. The tentative location of the chirally-complexed 
      aggregation on the HSA template was identified as the large interdomain cleft of 
      HSA, where carotenoid derivatives have been found to bind previously. Only weak 
      binding to AGP was observed. These results suggest that parenteral use of this 
      highly potent, water-dispersible astaxanthin-amino acid conjugate will result in 
      plasma protein association, and plasma protein binding at sites unlikely to 
      displace fatty acids and drugs bound at well-characterized binding sites on the 
      albumin molecule.
FAU - Zsila, Ferenc
AU  - Zsila F
AD  - Institute of Biomolecular Chemistry, Chemical Research Center, Budapest, PO Box 
      17, H-1525, Hungary.
FAU - Fitos, Ilona
AU  - Fitos I
FAU - Bikadi, Zsolt
AU  - Bikadi Z
FAU - Simonyi, Miklos
AU  - Simonyi M
FAU - Jackson, Henry L
AU  - Jackson HL
FAU - Lockwood, Samuel F
AU  - Lockwood SF
LA  - eng
PT  - Journal Article
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Buffers)
RN  - 0 (Dipeptides)
RN  - 0 (Ligands)
RN  - 0 (Orosomucoid)
RN  - 0 (Serum Albumin)
RN  - 0 (Solutions)
RN  - 0 (Xanthophylls)
RN  - 0 (astaxanthin dilysinate tetrahydrochloride)
RN  - 01YAE03M7J (beta Carotene)
RN  - 059QF0KO0R (Water)
SB  - IM
MH  - Buffers
MH  - Circular Dichroism
MH  - Dipeptides/chemical synthesis/*pharmacology
MH  - Humans
MH  - Ligands
MH  - Orosomucoid/*chemistry
MH  - Protein Binding
MH  - Serum Albumin/*chemistry
MH  - Solutions
MH  - Spectrometry, Fluorescence
MH  - Spectrophotometry, Ultraviolet
MH  - Stereoisomerism
MH  - Water
MH  - Xanthophylls
MH  - beta Carotene/*analogs & derivatives/chemical synthesis/*pharmacology
EDAT- 2004/09/30 05:00
MHDA- 2005/05/06 09:00
CRDT- 2004/09/30 05:00
PHST- 2004/07/02 00:00 [received]
PHST- 2004/08/06 00:00 [revised]
PHST- 2004/08/06 00:00 [accepted]
PHST- 2004/09/30 05:00 [pubmed]
PHST- 2005/05/06 09:00 [medline]
PHST- 2004/09/30 05:00 [entrez]
AID - S0960-894X(04)01021-2 [pii]
AID - 10.1016/j.bmcl.2004.08.013 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2004 Nov 1;14(21):5357-66. doi: 10.1016/j.bmcl.2004.08.013.