Biochemical characteristics and differentiating activity of 4-oxo analogs of retinoic acid.
3-Methyl-4-oxoretinoic acid and 3-cinnamyl-4-oxoretinoic acid bind to a cellular retinoic acid-binding protein (CRABP-II) and to a retinoic acid-receptor protein (RARa). These analogs of 4-oxoretinoic acid, as well as the parent compound, have less binding affinity than retinoic acid. Cotransfection assays in CV-1 cells with plasmids containing cDNAs for RAR alpha, RAR beta and RAR gamma (homodimers) and RAR alpha-RXR alpha and RAR beta-RXR alpha (heterodimers), indicate that 3-cinnamyl-4-oxoretinoic acid induces relatively less transcriptional activity than 4-oxoretinoic acid and its 3-methyl analog, both of which are less effective than retinoic acid. In differentiating mouse F9 embryocarcarcinoma cells, the order of effectiveness is retinoic acid > 4-oxoretinoic acid = 3-methyl-4-oxoretinoic acid > 3-cinnamyl-4-oxoretinoic acid. This order of potency is similar to that for inhibition of induction of ornithine decarboxylase (ODC) activity and for prevention of papillomas on the skin of mice. Binding to CRABP-II and activation of RARs appear to be important factors for expression of differentiating activity, inhibition of induction of ODC activity and prevention of papillomas on the skin of mice.
Sani
B P
BP
Southern Research Institute, Birmingham, Alabama 35255-5305, USA.
Venepally
P
P
Zhang
X K
XK
Hill
D L
DL
Shealy
Y F
YF
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002642:Chick Embryo; D004790:Enzyme Induction / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010212:Papilloma / Q000517:prevention & control; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012878:Skin Neoplasms / Q000517:prevention & control; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
C100571:3-cinnamyl-4-oxoretinoic acid; C100572:3-methyl-4-oxoretinoic acid; D065108:Ornithine Decarboxylase Inhibitors; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082928:retinoic acid binding protein II, cellular; C002202:4-oxoretinoic acid; D014212:Tretinoin; D009955:Ornithine Decarboxylase