all-trans-4-Oxoretinoic acid (all-trans 4-Keto Retinoic Acid)

4-oxo Retinoic acid is an active metabolite of the vitamin A metabolite and retinoic acid receptor (RAR) ligand all-trans retinoic acid .¹ It is formed from all-trans retinoic acid by several cytochrome P450 (CYP) isoforms, including CYP1A1, CYP3A7, and CYP26A1.^2,3 4-oxo Retinoic acid binds to RARα, RARβ, and RARγ (IC₅₀s = 59, 50, and 142 nM, respectively, in radioligand binding assays) and induces expression of a luciferase reporter in COS-7 cells expressing RARα, RARβ, or RARγ (EC₅₀s = 33, 8, and 89 nM, respectively).¹ It increases protein levels of cytokeratin 7 (CK-7) and CK-19 in human epidermal keratinocytes when used at a concentration of 1 ?M.⁴ 4-oxo Retinoic acid (10-1,000 nM) inhibits the proliferation of MCF-7 breast cancer cells.⁵ It is teratogenic to zebrafish embryos (EC₅₀ = 8.1 nM).⁶

1.Idrest, N., Marill, J., Flexor, M.A., et al.Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomersJ. Biol. Chem.277(25)31491-31498(2002) 2.Marill, J., Cresteil, T., Lanotte, M., et al.Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolitesMol. Pharmacol.58(6)1341-1348(2000) 3.Thatcher, J.E., Buttrick, B., Shaffer, S.A., et al.Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylaseMol. Pharmacol.80(2)228-239(2011) 4.Baron, J.M., Heise, R., Blaner, W.S., et al.Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitroJ. Invest. Dermatol.125(1)143-153(2005) 5.Van heusden, J., Wouters, W., Ramaekers, F.C.S., et al.All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitroBr. J. Cancer77(1)26-32(1998) 6.Pípal, M., Novák, J., Rafajová, A., et al.Teratogenicity of retinoids detected in surface waters in zebrafish embryos and its predictability by in vitro assaysAquat. Toxicol.246106151(2022)