13,14-Dihydroxy-retinol, a New Bioactive Retinol Metabolite (*)
- Fadila Derguini(1)(§),
- Koji Nakanishi(1),
- Ulrich Hämmerling(2),
- Ramon Chua(2),
- Thomas Eppinger(2),
- Ester Levi(2) and
- Jochen Buck(3)(¶)
- From the (1) Department of Chemistry, Columbia University, New York, New York 10027, the
- (2) Program of Immunology, Memorial Sloan-Kettering Cancer Center, and the
- (3) Department of Pharmacology, Cornell University Medical College, New York, New York 10021
- § To whom correspondence should be addressed. Present address: Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 382, New York, NY 10021. Tel.: 212-639-7522; Fax: 212-794-4019.
Abstract
Deprivation of vitamin A (retinol) leads to reduced potential of B cell proliferation and nearly complete block of T cell activation in vitro. Retinol, which is thought to function as a pro-hormone, is enzymatically converted into intracellular messenger molecules. Thus, 14-hydroxy-retro-retinol (14-HRR) is an intracellular messenger molecule linked to activation and growth regulation of lymphocytes; whereas, anhydroretinol, another natural retro-retinoid, is an antagonist of 14-HRR effects. In this article, we describe the isolation, structure determination, synthesis, and biological properties of a new intracellular retinol derivative, 13,14-dihydroxy-retinol (DHR), which also supports the viability of retinol-deprived lymphocytes. DHR is found in numerous cell lines representing a large cross-section of tissues and animals from insects to mammals. In T lymphocytes the production of DHR and 14-HRR is up-regulated by phorbol ester. DHR is converted to 14-HRR by mild acid treatment, but not by cells; therefore DHR is not a biosynthetic intermediate in the conversion of retinol to 14-HRR. DHR is a distinct end point of retinol metabolism. Although it is linked to cell proliferation, its biological role remains to be determined.
Footnotes
-
↵¶ Pew Scholar in the Medical Sciences.
-
↵* This work was supported by National Institutes of Health Grants GM-36564, JM-47599, CA-38351, and GM-45799. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- RA
-
retinoic acid
- 14-HRR
-
14-hydroxy-4,14-retro-retinol
- AR
-
anhydroretinol
- DHR
-
13,14-dihydroxy-retinol
- HPLC
-
high-pressure liquid chromatography
- PMA
-
phorbol myristate acetate
- EI/MS
-
electron impact/mass spectroscopy
- CI
-
chemical ionization.
-
↵2The low-resolution EI/MS shows the following peaks: mass-to-charge ratio m/z (%) 320 (50; M
), 302 (22; M − H2O), 284 (12; M − 2 
H2O), 272 (22; M − H20 − 2 
Me), 259 (100; M − CH[OH]CH2OH).
-
↵3We have chosen to show in Fig. 2 the natural DHR 1H NMR in CD3CN, because DHR decomposes slowly in CDCl3. However, the 1H NMR in CDCl3 is better resolved, and shows clearly that P1 is a mixture of diastereomers:
1.00 [s, 6H, 1-(CH3)2], 1.32/1.37 (2 s, 3H, 13-CH
), 1.44 (m, 2H, 2-H
), 1.59 (m, 2H, 3-H
), 1.67 (s, 3H, 5-CH
), 1.92 (s, 3H, 9-CH
), 1.98 (t, J=6 Hz, 2H, 4-H
), 3.49/3.56 (2 m, 1H, 14-H), 3.75 (m, 2H, 15-H
), 5.72/5.75 (2d, J=15 Hz, 1H, 12-H), 6.02 (d, J=11 Hz, 1H, 10-H), 6.04 (d, J=16 Hz, 1H, 8-H), 6.15 (d, J=16 Hz, 1H, 7-H), 6.74/6.75 (2dd, J=11 Hz, 15 Hz, 1H, 11-H).
-
- Received December 1, 1994.
- Revision received March 21, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
