Metabolism and transactivation activity of 13,14-dihydroretinoic acid.
The metabolism of vitamin A is a highly regulated process that generates essential mediators involved in the development, cellular differentiation, immunity, and vision of vertebrates. Retinol saturase converts all-trans-retinol to all-trans-13,14-dihydroretinol (Moise, A. R., Kuksa, V., Imanishi, Y., and Palczewski, K. (2004) J. Biol. Chem. 279, 50230-50242). Here we demonstrate that the enzymes involved in oxidation of retinol to retinoic acid and then to oxidized retinoic acid metabolites are also involved in the synthesis and oxidation of all-trans-13,14-dihydroretinoic acid. All-trans-13,14-dihydroretinoic acid can activate retinoic acid receptor/retinoid X receptor heterodimers but not retinoid X receptor homodimers in reporter cell assays. All-trans-13,14-dihydroretinoic acid was detected in vivo in Lrat-/- mice supplemented with retinyl palmitate. Thus, all-trans-13,14-dihydroretinoic acid is a naturally occurring retinoid and a potential ligand for nuclear receptors. This new metabolite can also be an intermediate in a retinol degradation pathway or it can serve as a precursor for the synthesis of bioactive 13,14-dihydroretinoid metabolites.
Moise
Alexander R
AR
Department of Ophthalmology, University of Washington, Seattle, Washington 98195, USA.
Kuksa
Vladimir
V
Blaner
William S
WS
Baehr
Wolfgang
W
Palczewski
Krzysztof
K
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D013053:Spectrophotometry; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays; D014801:Vitamin A / Q000378:metabolism
C503916:13,14-dihydroretinoic acid; D000447:Aldehydes; D018076:DNA, Complementary; D047488:Retinoid X Receptors; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D010100:Oxygen