Retinoids: Molecular and Metabolic Aspects Part A

584 Pages·1990·11.305 MB·English

by  Abelson J. (ed.), Simon M. (ed.), Sies H. (ed.)

METHODS IN ENZYMOLOGY
EDITORS-IN-CHIEF
John N. Abelson Melvin I. Simon
DIVISIOOFN BIOLOGY
CALIFORNIIAN STITUTOEF TECHNOLOGY
PASADENA, CALIFORNIA
FOUNDING EDITORS
Sidney P. Colowick and Nathan 0. Kaplan
Methods in Enzymology
Volume 189
Ret&oids
Part A
Molecular and Metabolic Aspects
EDITED BY
Lester Packer
OF DEPARTMENT AND MOLECULAR CELL BIOLOGY
UNIVERSITY OF CALIFORNIA, BERKELEY
BERKELEY, CALIFORNIA
lairotidE Board Advisory
Frank Chytil Leonard Milstone
DeWitt Goodman Concetta Nicotra
Maria A. Livrea James A. Olson
Stanley S. Shapiro
ACADEMIC PRESS, INC.
Harcourt Brace Jovanovich, Publishers
San Diego New York Boston
London Sydney Tokyo Toronto
Preface
Spectacular progress and unprecedented interest in the field of reti-
noids prompted us to consider this topic for two volumes in the Methods
in Enzymology series: Volume 189, Retinoids, Part A: Molecular and
Metabolic Aspects and Volume 190, Retinoids, Part B: Cell Differentia-
tion and Clinical Applications.
From a historical perspective we know that studies in the 1930s
showed that vitamin A (retinol) and retinal had a role in the visual pro-
cess. It was also recognized that some link between vitamin A and
cancer incidence existed. Several decades ago it was discovered that
retinoic acid had a dramatic effect on the chemically induced DMBA
mouse skin carcinogenesis model in which enormous reductions in the
tumor burden were observed. This led to the realization that retinoids had
important effects on cell differentiation. This resulted almost immediately
in the synthesis and evaluation of new retinoids. Indeed, the effects of
retinoids on cell differentiation appear to be more universal and of greater
importance than their light-dependent role in vision and microbial energy
transduction.
Progress has been rapid, and the importance of accurate methodology
for this field is imperative to its further development. The importance of
methodology applies to the use of retinoids in basic research in molecular,
cellular, and developmental biology, and in clinical medicine. In medi-
cine, applications have been mainly to cancer and in dermatology to the
treatment of skin diseases and skin aging. As new retinoids are being
tested in biological models and in clinical medicine, interest in the nutri-
tion and pharmacology of retinoids has arisen. Moreover, the beneficial
effects of retinoids in pharmacological treatment have led to a recognition
of the "double-edged sword" of toxicity (teratogenicity).
In Section I of this volume, Structure and Analysis, retinoid structure,
stability, photosensitivity characteristics, and analytical procedures are
included. Section II, Receptors, Transport, and Binding Proteins, focuses
on protein isolation and the current status of methods for characteriza-
tion, assay, and distribution. As the role of binding proteins is not com-
pletely clear and new ones are still being identified, the methods for
investigating their presence are of importance. In particular, different
types of nuclear receptors for retinoic acid having sequence homologies
with hormones have increased interest in this area, and the role of nuclear
receptors in retinoid-modulated gene expression is an area that is under
rapid development. In Section III, Enzymology and Metabolism, retinoid
XV
Contributors to Volume 189
elcitrA srebmun era ni parentheses gniwollof the seman of .srotubirtnoc
snoitailiffA listed era .tnerruc
ABARZOA PATRICIO (35), Department of -nO THEODORE R. BREITMAN (23), Laboratory
cology and Virology, Roche Research of Biological Chemistry, Division of Can-
Center, Nutley, New Jersey 01170 cer Treatment, National Institute, Cancer
National Institutes of Health, Bethesda,
ALICE J. ADLER (21), Eye Research Insti-
Maryland 29802
tute, Boston, Massachusetts 41120
N. R. AL-MALLAH (16), Laboratoire de C. D. B. BRIDGES (5, 20, 33), Department of
Pharmacocin~tique et Toxicocindtique, Biological Sciences, Purdue University,
Facultd de Pharmacie, Marseille, 13385 West Lafayette, Indiana 47907
Cedex 5, France
MELISSA K. BUELT (38), Department of Bio-
C. AUBERT (16), Laboratoire de Pharmaco- chemistry, University of Minnesota, St.
cin~tique et Toxicocindtique, Facultd de Paul, Minnesota 80155
Pharmacie, 13385 MarseiUe, Cedex 5,
H. BUN (16), Laboratoire de Pharmaco-
France
cindtiqae et Toxicocindtique, Facaltd de
JOItN STUART BAILEY (37), Banting and Pharmacie, 13385 Marseille, Cedex 5,
Best Department of Medical Research,
France
University of Toronto, Toronto, Ontario
M5G IL6, Canada CHRISTER BUSCH (32), Department of Pa-
thology, Uppsala University, S-751 58
MARK D. BALL (50), Department of Chemis-
Uppsala, Sweden
try, Rose-Hulman Institute of Technol-
ogy, Terre Haute, Indiana 30874 LOUISE M. CANFIELD (45), Department of
FAAN WEN BANGERTER (44), Department of Biochemistry, University of Arizona, Tuc-
Biological Chemistry and Molecular son, Arizona 12758
Pharmacology, Harvard Medical School,
J. P. CANO (16), Sanofi Recherche, 28043
Boston, Massachusetts 51120
Montpellier, France
ARUN B. BARUA (13), Department of Bio-
GERALD J. CHADER (21), Laboratory of Ret-
chemistry and Biophysics, Iowa State
Cell inal and Molecular Biology, National
University, Ames, I o11w0a0 5
Eye Institute, National Institutes of
DAVID A. BERNLOHR (38), Department of Health, Bethesda, Maryland 29802
Biochemistry, University of Minnesota,
RONALD F. CHILDS (l 1), Department of
St. Paul, Minnesota 80155
Chemistry, McMaster University, Hamil-
PAUL S. BERNSTEIN (56), Jules Stein Eye
ton, Ontario LSS 4L8, Canada
Institute, School of Medicine, University
of California at Los Angeles, Los LAURIE L. CHINANDER (38), Department of
Angeles, California 42009 Biochemistry, University of Minnesota,
St. Paul, Minnesota 80155
HANS K. BIESALSKI (18), Department of
Physiological Chemistry and Pathobio- ANDREW J. CLIFFORD (9), Department of
chemistry, University of Mainz, D-6500 Nutrition, University of California at
Mainz, Federal Republic of Germany Davis, Davis, California 61659
WILLIAM S. BLANER (19, 27), Institute of DALE A. COOPER (55), Edible liO Products
Human Nutrition, Columbia University, Division, Procter & Gamble Company,
New York, New York 23001 Cincinnati, Ohio 42254
xi
xii CONTRIBUTORS TO VOLUME 189
FgANS J. M. (43), DAEMEN Department of lege of Physicians and Surgeons, New
Biochemistry, University of N(imegen, York, New York 23001
0056 HB Nijmegen, The Netherlands YREFFEJ I. (58), GORDON Departments of
ANN K. (24, 31), DALY Department of Phar- Medicine, Biochemistry and Molecular
macological Sciences, University of New- Biophysics, Washington University
castle upon Tyne, Medical School, New- School of Medicine, St. Louis, Missouri
castle upon Tyne NE2 4HH, England 01136
M. I. (2), DAWSON Life Sciences Division, GEgHART RENPUARG (26), La Jolla Cancer
SRI International, Menlo Park, Califor- Research Foundation, La Jolla, Califor-
nia 52049 nia 62129
WILLEM J. ED GRIP (43), Department of HPESOJ F. (25), GRIPPO Department of -ixoT
Biochemistry, University of Nijmegen, cology and Pathology, Hoffman-La
0056 HB Nijmegen, The Netherlands Roche Ltd., Nutley, New Jersey 01170
ANDREW P. DE (4, LEENHEER 10), Labora- MARY LOU GURLER (60), Department of
toria voor Medische Biochemie en voor Oncology and Virology, Roche Research
Klinische Analyse, Rijksuniversiteit Gent, Center, Nutley, New Jersey 01170
Gent, B-9000 Belgium
EARL H. HARRISON (52), Department of
ULF (32), ERIKSSON Ludwig Institute for Physiology and Biochemistry, The Medi-
Cancer Research, Stockholm Branch, cal College of Pennsylvania, Philadel-
S-104 1O Stockholm, Sweden phia, Pennsylvania 92191
RONALD M. EVANS (22), Howard Hughes SAMOaIT HERMANN (26), La Jolla Cancer
Medical Institute, The Salk Institute for Research Foundation, La JoUa, Califor-
Biological Studies, La Jolla, California nia 62129
83129
DLANOD L. HILt (3), Biochemistry Depart-
NAROG FEX (42), Department of Clinical
ment, Southern Research Institute, Bir-
Chemistry, University Hospital of Lund,
mingham, Alabama 55253
122-S 58 Lund, Sweden
P. D. HoBBs (2), Life Sciences Division, SRI
SHAO-LING FONG (20, 33), Department of
International, Menlo Park, California
Ophthalmology, Indiana University, Indi-
52049
anapolis, Indiana 20264
ANTON M. JETTEN (25), Cell Biology
SAMOHT A. FRITZ (45), Department of Bio-
Group, Laboratory of Pulmonary Patho-
chemistry, University of Arizona, Tucson,
biology, National Institute of Environ-
Arizona 12758
mental Health Sciences, Research -nairT
(32), FUNA KEIKO Ludwig Institute for Can-
gle Park, North Carolina 90772
cer Research, University Hospital, S-751
58 Uppsala, Sweden ROVNUG NOSSENNAHOJ (42), Department of
Clinical Chemistry, University Hospital
DLORAH C. (8, FURR 9) Department of Bio-
of Lund, S-221 58 Lund, Sweden
chemistry and Biophysics, Iowa State
University, Ames, I o11w0a0 5 A. (9), JONES DANIEL Facility for Advanced
Instrumentation, University of California
L. E. REBREG (47), Department of Food Sci-
at Davis, Davis, California 61659
ence and Nutrition, University of Rhode
Island, Kingston, Rhode Island 18820 T. (28), JONES ALWYN Institute for Molecu-
VINCENT ER,~UGIG (22), Division of Endo- lar Biology, Biomedical Center, Uppsala
crinology, Research Institute, Hospi- The University, 24 S-751 Uppsala, Sweden
tal for Sick Children, Toronto, Ontario PERE JULI)~ (48), Departament de
M5G 1](8, Canada Bioquimica i Biologia Molecular, Fa-
DEWITT S. NAMDOOG (19, 29), Department cultat de ,seicnOiC Universitat AutOnoma
of Medicine, Columbia University, Col- de Barcelona, Barcelona, 08193 Spain
CONTRIBUTORS TO VOLUME 189 xiii
ECNERWAL A. (15), KAPLAN Department of Standards and Technology, Gaithers-
Pathology, Bellevue Hospital Medical burg, Maryland 99802
Center, New York, New York 6IOOI PAUL N. (51), MACDONALD Department of
ASAMIHCIM (34), KATO First Department of Biochemistry, University of Arizona, Tuc-
Internal Medicine, Gifu University School son, Arizona 42758
of Medicine, Tsukasa-machi ,04 Gifu ,005 DRANREB MARTIN (24), Centre Interna-
Japan tional De Recherches Dermatologiques,
MICHAEL KLAU(S1 ), Department of Phar- Sophia Antipolis, 06565 Valbomme, -eC
maceutical Research, Hoffmann-La dex, France
Roche Ltd., Basel, CH-4002 Switzerland VALERIE MATARESE (38), Department of
M. wAR NAMHSKAL (46), Lipid Research Biochemistry, University of Minnesota,
Laboratory, Veterans Administration St. Paul, Minnesota 80155
Medical Center, Washington, D.C. 22402 JUDITH A. MILLER (15), Medical Research
Laboratories, Cincinnati, Ohio 91254
WILLY E. LAMBERT (10), Laboratoria voor
Medische Biochemie en voor Klinische IHSOTUSAY (34), MUTO Department First of
Analyse, RUksuniversiteit Gent, B-9000 Internal Medicine, Gifu University School
Gent, Belgium of Medicine, Tsukasa-machi ,04 Gifu ,005
Japan
YRAG M. (6), LANDERS Jules Stein Eye In-
stitute, UCLA School of Medicine, Los HPESOJ L. (52, NAPOLI 53), Department of
Angeles, California 42009 Biochemistry, School of Medicine and
Biomedical Sciences, ehT State Univer-
NEGREUJ M. (26), LEHMANN La Jolla Can-
sity of New York at Buffalo, Buffalo, New
cer Research Foundation, La Jolla, Cali-
York 41241
fornia 62129
H. J. (4), NELIS Laboratoria Medische voor
M. A. LEO (54, 59), Department of Medi-
Biochemie en voor Klinische Analyse,
cine, Mount Sinai School of Medicine,
Rijksuniversiteit Gent, B-9000 Gent,
City University of New York, New York,
Belgium
New York 12001
CLARA NERVI (25), Cell Biology Group,
CRAM S. LEVlN (58), Department of Medi-
Laboratory of Pulmonary Pathobiology,
cine, Washington University School of
National Institute of Environmental
Medicine, St. Louis, Missouri 01136
Health Sciences, Research Park, Triangle
ELLEN LI (58), Departments of Medicine, North Carolina 90772
Biochemistry and Molecular Biophysics,
AICRAM NEWCOMER (28), Department of
Washington University School of Medi-
Biochemistry, Vanderbilt University
cine, St. Louis, Missouri 01136
School of Medicine, Nashville, Tennessee
C. S. (54, LIEBER 59), Department of Medi- 23273
cine and Pathology, Mount Sinai School HANS REDNILDRON (32), Department of Pa-
of Medicine, City University of New York, thology, Uppsala University, S-751 58
New York, New York 12001 Uppsala, Sweden
IHS-GNEHZ LIN (33), Department of Neuro- AKATASAM OKUNO (34), First Department
biology and Behavior, State University of of Internal Medicine, Gifu University
New York at Stony Brook, Stony Brook, School of Medicine, Tsukasa-machi ,04
New York 49711 Gifu 500, Japan
MARIA A. LIVREA (39, 57), Istituto di SEMAJ ALLEN OLSON (46), Department of
Biologica, Chimica Palermo Universitd di Biochemistry and Biophysics, Iowa State
Policlinico, Palermo, 90127 Italy University, Ames, Iowa 11005
WILLIAM A. NAHERCCAM (17), Organic An- DAVID E. GNO (51), Department of Bio-
Research alytical Division, Center for An- chemistry, Vanderbih University, Nash-
alytical Chemistry, National Institute of ville, Tennessee 23273
xiv CONTRIBUTORS TO VOLUME 981
XAVIER PARI~S (48), Departament de ment of Biochemistry, Temple University
Bioquimica i Biologia Molecular, Fa- School of Medicine, Philadelphia, Penn-
cultat de Cidncies, Universitat sylvania 04191
Aut~Snoma de Barcelona, 08193 Barce- MEIR J. REFPMATS (15), Department of Epi-
lona, Spain demiology, Harvard Medical School of
SUNGAM PFAHL (26), La Jolla Cancer Re- Public Health, and The Channing Labo-
search Foundation, La Jolla, California ratory, Harvard Medical School and
62129 Brigham and Woman's Hospital, Boston,
TREBOR R. RANDO (44, 56), Department of Massachusetts 51120
Biological Chemistry and Molecular EVAN A. STEIN (15), Medical Research
Pharmacology, Harvard Medical School, Laboratories, Cincinnati, Ohio 91254
Boston, Massachusetts 02115 (40, WILLIAM STILLWELL 41), Department
REHPOTSIRHC P. F. (24, REDFERN 31), De- of Biology, Indiana University--Purdue
partment of Dermatology, University of University at Indianapolis, Indianapolis,
Newcastle upon Tyne, Newcastle upon Indiana 50264
Tyne NE1 4LP, England OKIRON IHSAHAKAT (23), Laboratory of Bi-
A. (7, ROSS 49), CATHARINE Department of ological Chemistry, Division of Cancer
Physiology and Biochemistry, Medical Treatment, National Cancer Institute,
College of Pennsylvania, Philadelphia, National Institutes of Health, Bethesda,
Pennsylvania 92191 Maryland 29802
AHPSUP (32), SAKENA Department of Pa- SAMOHT E. (45), TARARA Department of
thology, Uppsala University, Uppsala, Biochemistry, University of Arizona, Tuc-
Sweden son, Arizona 12758
AMHARB P. SANI (3, 36), Biochemistry De- LUISA TESORIERE (39, 57), lstituto di
partment, Southern Research Institute, Chimica Biologica, Universit6 di Palermo
Birmingham, Alabama 35255 Policlinico, 90127 Palermo, Italy
GARY S. SHAW (ll), Department of Bio- MATY NAMREKUZT (26), La Jolla Cancer
chemistry, University of Alberta, Edmon- Research Foundation, La Jolla, Califor-
ton, Alberta T6G 2H7, Canada nia 62129
LEAHCIM I. NAMREHS (35, 60), Department NEHPETS R. LLASSAW (40, 41), Department
of Oncology and Virology, Roche Re- of Physics, Indiana University--Purdue
search Center, Nutley, New Jersey 07110 University at Indianapolis, Indianapolis,
HCIROEIRF (12), SIEBERT Max-Planck-lnsti- Indiana 46205
tut ffir Biophysik, D-6000 Frankfurt am ARABRAB TREGGIW (21), Laboratory of Ret-
Main, Federal Republic of Germany inal Cell and Molecular Biology, National
SEGROEG RELAHTNEGEIS (30, 61), Clinique Eye Institute, National Institutes of
Dermatologie, HOpital Cantonal Univer- Health, Bethesda, Maryland 29802
sitaire, CH-1211 Geneva, Switzerland KEN N. WILLS (26), La Jolla Cancer Re-
K. L. (47), SIMPSON Department of Food search Foundation, La Jolla, California
Science and Nutrition, University of 62129
Rhode Island, Kingston, Rhode Island RONALO WYSS (14), Department of Drug
1882O Metabolism, Pharmaceutical Research,
CHI-HUNG SIU (37), Banting and Best De- Hoffmann-La Roche Ltd., CH-4002B a-
partment of Medical Research, Univer- sel, Switzerland
sity of Toronto, Toronto, Ontario MSG NUK-OAIX (26), ZHANG La Jolla Cancer Re-
1L6, Canada search Foundation, La Jolla, California
DIANNE ROBERT SOPRANO (29), Depart- 62129
]1[
STRUCTURE OF RETINOIDS 3
[1] Structure Characteristics of Natural and
Synthetic Retinoids
By KLAUS MICHAEL
Introduction
The term retinoids comprises the natural occurring vitamin A deriva-
tives such as retinol, retinal, and retinoic acid as well as the large number
of synthetic analogs prepared since the late 1960s, regardless of whether
they have biological activity, i The goal of this intensive effort at synthesis
in academia as well as in the pharmaceutical industry was to improve on
the ratio of toxic effects (e.g., hypervitaminosis A) to therapeutic activity
compared to retinoic acid. In addition, compounds with better selectivity
toward the various therapeutic indications (dermatology, oncology, rheu-
matology, immunology) have been sought.
Structure of Retinoids
Formally the molecule of retinoic acid consists of three main sections:
a lipophilic part at one end, connected via a polyunsaturated chain as a
spacer to a hydrophilic group at the other end of the molecule (Fig. .)1 All
three parts have been modified extensively. In the following a selection of
compounds with typical variations is given.
Changes ni Hydrophilic Part
Different Oxidation Level of Polar End Group. Compounds in which
the oxidation level of the polar end group is different include the natural
vitamin A derivatives retinol (1), retinal (2), retinoic acid (3), and close
analogs such as esters (4) and amides (5). Because the free acid is gener-
ally considered to be the active principle, for ni vitro experiments only
compounds with a carboxylic acid end group should be used. Esters and
~
CHO
OH
1 2
M. B. Sporn and A. B. Roberts, Ciba Found. Symp. 113, 1 (1985).
Copyright © 1990 by AcademPirce ss, Inc.
METHODS IN ENZYMOLOGY, VOL. 981 All rights of reproduction in any form reserved.
4 ~ STRUCTURE AND ANALYSIS ]1[
CO2H
lipophilic spacer hydrophilic
part part
Fro. 1. Structural subunits of the retinoic acid molecule.
amides may be inactive owing to their stability toward hydrolysis under
the experimental conditions.
Other Polar Groups. The carboxylic acid end group of retinoic acid (3)
has been replaced by other acidic or polar moieties. Examples are sul-
fonic and phosphonic acid derivatives 6 and 7, 2 sulfone 8, 2 diketo deriva-
tive 9, 3 and the phenol 10. 4
~
~,~~O2CaH5
~ 3 ~ 4
0
SO2OC2H 5
NHCaH5
6
5 ~
0
SO2C2H5
7 8
9 lO
2 M. Klaus, unpublished (1982 and 1984).
3 N. Acton, A. Brossi, D. L. Newton, and M. B. Sporn, J. Med. Chem. 23, 805 (1980).
4 B. Loev and W.-K. Chan, U.S. Patent 4,605,675 (1986).
[1] ERUTCURTS FO SDIONITER 5
Changes ni Lipophilic Part
Pattern Substitution of Ring. Cyclohexenyl The group of analogs with
an altered substitution pattern of the cyclohexenyl ring consists mainly of
oxygenated metabolites of retinoic acid, for example, 4-hydroxyretinoic
acid (11), 5 18-hydroxyretinoic acid (12), 6 and 5,6-epoxyretinoic acid
(13), 7 but also comprises compounds such as 14 and 15.
HO 11 HO 21
H20C O ~ H2OC
31 14
H2OC
51
Aromatization of Ring. Cyclohexenyl Replacement of the trimethylcy-
clohexenyl group with a suitably substituted benzene ring leads to com-
pounds such as etretinate (16) and motretinid (17) 8 having an increased
therapeutic index. A certain lipophilicity in this part of the molecule
seems to be necessary for biological activity. The unsubstituted analog 18
is virtually inactive in most of the relevant test systems.
0
C H 3 ~ 5H2c2Oc
03HC ~ v .x
16 ~ 71
C02H
18
5 .M Rosenberger, J. Org. Chem. ,74 8961 .)2891(
6 .M Rosenberger and C. Neukom, J. Org. Chem. ,74 2871 .)2891(
K. 7 .V John, .M .R Lakshrnanan, and H. .R Cama, Biochem. J. 103, 935 .)7691(
H. Mayer, 8 .W Bollag, .R ,inni~H and .R ,ggeifR Experientia ,43 5011 .)8791(