Chemically induced isomerization and differential uptake modulate retinoicacid disposition in HL-60 cells

Citation
C. Lanvers et al., Chemically induced isomerization and differential uptake modulate retinoicacid disposition in HL-60 cells, FASEB J, 12(15), 1998, pp. 1627-1633
Citations number
40
Categorie Soggetti
Experimental Biology
Journal title
FASEB JOURNAL
ISSN journal
08926638 → ACNP
Volume
12
Issue
15
Year of publication
1998
Pages
1627 - 1633
Database
ISI
SICI code
0892-6638(199812)12:15<1627:CIIADU>2.0.ZU;2-P
Abstract
The successful introduction of 13-cis-retinoic acid (13-cis-RA) and all-tra ns-retinoic acid (all-trans-RA) in the chemoprevention and treatment of can cer along with the discovery of different retinoic acid receptors transacti vated by different retinoic acid isomers resulted in a number of in vitro s tudies of the antitunor effects of single retinoic acid isomers, Since the formation of retinoic acid isomers with different receptor affinities might modulate retinoic acid response in vitro, we determined retinoic acid disp osition in HL-60 cells and cell culture medium during incubation with 13-ci s-, 9-cis-, and all-trans-RA, In medium, retinoic acids underwent a thiol-r adical mediated isomerization resulting in a mixture of 13-cis-, 9-cis-, 9, 13-di-cis-, and all-trans-RA. Except for the 9,13-di-cis-RA, all isomers ge nerated in medium were also detected in HL-60 cells. Whereas 9-cis-RA and 1 3-cis-RA showed similar cellular pharmacokinetics, all-trans-RA reached abo ut fourfold higher concentrations in HL-60 cells com pared to 9-cis-RA and 1-3cis-RA. Due to its better uptake, all-trans-RA. became the main isomer w ithin cells as it was formed in the medium when incubated with 13-cis-RA an d 9-cis-RA. Thus, due to the simple chemically induced isomerization and it s profound influence on cellular retinoic acid concentrations, studies of t he efficacy of single retinoic acid isomers in vitro should be interpreted with caution.