Table Of ContentF. Marks, G. Furstenberger (Eds.)
Prostaglandins, Leukotrienes
and Other Eicosanoids
F. Marks, G. Furstenberger (Eds.)
Prostaglandins ,
Leukotrienes and
Other Eicosanoids
From Biogenesis to Clinical Application
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I LEY-VCH
-
Weinheim New York Chichester
Brisbane Singapore Toronto
Prof. Dr. Friedrich Marks
Dr. Gerhard Furstenberger
Abteilung Biochemie der gewebsspezischen Regulation (BOSOO)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
D-69120 Heidelberg
This book was carefully produced. Nevertheless, editors, authors and publisher do not
warrant the information contained therein to be free of errors. Readers are advised to
keep in mind that statements, data, illustrations, procedural details or other items may
inadvertentlv be inaccurate.
Library of Congress Card No.: applied for
A catalogue record for this book is available from the British Library.
Deutsche Bibliothek Cataloguing-in-Publication Data:
Prostaglandins, leukotrienes and other eicosanoids: from biogenesis to clinical application I
Friedrich Marks; Gerhard Fiirstenberger (ed.). - Weinheim; New York; Chichester; Brisbane;
Singapore; Toronto: Wiley-VCH, 1999
ISBN 3-527-29360-4
0 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany). 1999
Printed on acid-free and chlorine-free paper.
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Preface
Although discovered more than 65 and identified more than 30 year ago, eicosanoids
were considered for a long time to represent biocompounds of minor importance, for
instance , when compared with hormones and cytokines. As a consequence eicosa-
noid research was regarded as a subject for narrow specialist rather than being a ma-
jor field in biomedical science. This situation has changed completely, since mainly
due to the impact of modern analytical and molecular-biological technology, eicosa-
noids have become recognized as a physiologically and pathologically very important
family of cellular signal transducers; this also underlined by two Nobel prizes.
Eicosanoids and related fatty acid derivatives are produces throughout the eukary-
otic kingdom by probably every organism and every cell type. Most of these com-
pounds fulfill the functions of local mediators, also called autocoids or tissue hor-
mones. As such they modulate the effects of all kinds of hormonal, immunological,
and nervous signals as well as of environmental influences. in fact, the eicosanoid
system may be understood as a device of biological signal transduction and signal
processing which is placed between the environment and the systemic network of
signaling on the one side and the intracellular machinery of signal processing on the
other side. At the level of the molecular mechanism of prostanoid action there are
indeed fluid transitions between extra- and intracellular signaling. The enormous
versatility of eicosanoids is a result of the extraordinary multiplicity of poly-
unsaturated fatty acid metabolism that leads to innumerable bioactive compounds,
which are still far from being known as a whole. This metabolic complex certainly
represent one of the most fascinating examples of biochemical evolution in nature. It
appears as if eicosanoids - together with other local mediators - form a highly sophis-
ticated network of locally restricted inter- and intracellular communication which is
not fixed but becomes organized 'on demand. The high degree of multiplicity and
feedback interactions indicate that this machinery operates in a non-linear fashion
which may help to produces 'order in chaos', that is, to carry out a characteristic per-
formance of living matter.
Considering the central role eicosanoids and related compounds play in cellular
(patho)-physiology it is everything but surprising that both basic research and phar-
maceutical industry undertake tremendous efforts in the development of drugs which
interact with this metabolic complex. As a major milestone in this field the identifica-
tion of nonsteroidal antiinflammatory drugs, such as aspirin, as inhibitors of prosta-
noid biosynthesis has to be mentioned. Today most investigators and clinicians agree
that an in-depth elucidation of eicosanoid metabolism is a prerequisite not only for an
understanding but also for an advanced treatment or prevention of some of the most
serious diseases, such as atherosclerosis, cancel, Alzheimer's dementia, allergic
asthma, and others.
This opinion is reflected by the chapters of this book. Following an introductory
VI Prejace
overview (Chapter I), Chapters 2-6 deal with the major enzymatic routes of eicosa-
noid biosynthesis, while Chapter 7-12 focuss on clinical aspects. The selection of
topics may appear to be rather arbitrary. However, considering the enormous and
rapidly enlarging extent of the field, any attempt to reach completeness would have
been doomed to failure from the very beginning. Thus, the selection of the topics had
to aim necessarily at exemplarity, and the goal of this book is to provide an introduc-
tion into, rather than a comprehensive review, of the field. As a compensation the
authors have done their best in providing up-dated reference lists which may help the
reader to follow-up special aspects in more detail and to the roots. Notwithstanding
these joint intentions, every contribution reflects the authors' personal approach to
handle the subject as far as style, arrangement, content, in-depth treatment, and the
emphasis on special aspects are concerned. Since every chapter should stand by itself
some overlapping and redundancy was inavoidable.
As a whole the book offers a snapshot of one of the most fascinating subjects of
current biological research and its clinical applications. The editors are aware of the
fact that in such a rapidly developing fields ideas, hypotheses, conclusions, and the
latest information are highly perishable goods. Nevertheless, they hope that the book
contains a substantial wealth of hard facts and, thus, will serve for a reasonable period
of time as a stimulation and guidance for both students and experts.
Heidelberg, June 1999 Friedrich Marks Gerhard Fiirstenberger
Cont ents
1 Arachidonic acid and companions:
................................................
an abundant source of biological signals 1
Friedrich Murks
1.1 The world of PUFAs .................................................................................. 1
The discovery of prostaglandins and related eicosanoids .......................... 3
1.2
Mammalian eicosanoids. ............................................................................ 6
1.3
Free arachidonic acid: a signaling compound? .......................................... 7
1.3.1
1.3.2 Prostanoids ................................................................................................. 8
1.3.3 HPETEs, HETEs and leukotrienes. .......................................................... 11
Lipoxins ................................................................................................... 15
1.3.4
1.3.5 15-Epi-lipoxins.. ....................................................................................... 17
1.3.6 Hepoxilins ................................................................................................ 18
1.3.7 Monooxy genase-derived eicosanoids ...................................................... 20
1.3.8 Isoprostanes .............................................................................................. 21
Anandam& ............................................................................................. 24
1.3.9
1.4 Eicosanoids in invertebrates. .................................................................... 27
1.5 Eicosanoid-related signaling compounds in plants .................................. 30
The cellular functions of eicosanoids in mammals .................................. 34
1.6
1.6.1 Eicosanoids as local mediators. ................................................................ 34
1.6.2 Specific membrane receptors mediate many biological
effects of eicosanoids ............................................................................... 35
1.6.3 Nuclear eicosanoid receptors: a new frontier in research. ........................ 38
1.7 Addendum: Methods of eicosanoid research ........................................... 40
1.8 References. ............................................................................................... 40
...............................................
2 The generation of free arachidonic acid 47
Peter Dieter
2.1 Introduction .............................................................................................. 47
2.2 (Re)Incorporartiono f arachidonic acid into phospholipids ..................... 48
2.3 Phospholipases A ..................................................................................... 49
2.3.1 Phospholipase A, ..................................................................................... 49
2.3.2 Phospholipases A2 .................................................................................... 49
2.3.2.1 Secretory phospholipases A2 .................................................................... 51
2.3.2.2 Cytosolic phospholipase A2 ..................................................................... 52
2.3.2.3 Calciurn-independent phospholipases A2. ................................................ 56
2.4 DAG lipase and PLC or PLDPA phosphohydrolase. .............................. 56
VIII Contents
2.5 Cellular models ........................................................................................ 57
2.5.1 P388D1m acrophages ............................................................................... 57
2.5.2 Rat liver macrophages. ............................................................................. 57
2.6 Conclusions .............................................................................................. 58
2.7 References.. .............................................................................................. 59
.....................................................................................
3 Cy clooxygenases 65
Karin Miiller-Decker
3.1 Introduction .............................................................................................. 65
3.2 Cloning of cyclooxygenase isoforms ....................................................... 66
3.3 Cyclooxygenase gene structures .............................................................. 67
3.4 Regulation of cyclooxygenase isoenzyme expression ............................. 69
3.5 Cyclooxygenase proteins ......................................................................... 73
3.5.1 Sequence comparisons ............................................................................. 73
3.5.2 Post-translational modification ................................................................ 74
3.5.3 X-ray analysis of crystal structure. ........................................................... 74
3.5.4 Subcellular localization ............................................................................ 75
3.6 Coupling of COX isoenzymes with phospholipases A2 ........................... 76
3.7 Substrate specificities. .............................................................................7. 7
3.8 Mechanism of enzyme catalysis ............................................................... 78
3.9 Biological functions of COX isoforms. .................................................... 79
3.10 Isoenzyme-specific inhibitors .................................................................. 81
3.11 References ................................................................................................ 83
..............................................................................
4 Prostanoid synthases 89
Christian Martin and Volker Ullrich
4.1 Introduction .............................................................................................. 89
4.2. Thromboxane A2 synthase ....................................................................... 91
4.3 Prostacyclin synthase ............................................................................... 93
4.4 Prostaglandin D syntase ........................................................................... 97
4.5. Prostaglandin E synthase. ......................................................................... 99
4.6 Prostaglandin F synthase. ....................................................................... 100
4.7 Glutathione S-transferases ..................................................................... 101
4.8 Detection of prostaglandin synthases in various tissues ........................ 102
4.9 Summary and outlook ............................................................................ 104
4.10 References. ............................................................................................. 104
.......................................................................................
5 Lipoxygenases 109
Hartmut Kiihn
5.1. lntroduction. ........................................................................................... 109
Contents IX
5.2. Lipoxygenase reaction ........................................................................... 110
5.3. Common properties of lipoxygenases .................................................... 111
5.4. Classification of lipoxygenases .............................................................. 113
5.5 Structural aspects of lipoxygenases ....................................................... 115
5.5.1. X-ray crystallography. ............................................................................ 115
5.5.2 Substrate alignment and determinants of positional specificity ............. 118
5.6 5-Lipoxygenases .................................................................................... 120
5.6.1 Enzymatic properties.,. ........................................................................... 120
5.6.2 5-Lipoxygenase activating protein ........................................................ 122
5.6.3 Molecular biology of 5-lipoxygenases. .................................................. 123
5.6.4 Tissue distribution and regulation of 5-LOX expression ....................... 123
5.6.5 Biological functions of 5-lipoxygenases ................................................ 124
5.7 12-Lipoxygenases. ................................................................................. 125
5.7.1 Subclassification and enzymatic properties ........................................... 125
5.7.2 Molecular biology of 12-lipoxygenases. ................................................ 126
5.7.3 Tissue distribution and regulation of 12-LOX expression ..................... 127
5.7.4 Biological functions of 12-lipoxygenases. ............................................. 127
5.8 Mammalian 15 -1ipoxygenases .............................................................. 129
5.8.1 Subclassification and enzyme properties ............................................... 129
5.8.2 Molecular biology of the reticulocyte-type 15-lipoxygenases. ..............1 30
5.8.3 Tissue distribution and regulation of 15-LOX expression ..................... 131
5.8.4 Biological functions of 15-lipoxygenases. ............................................. 132
5.8.4.1 Structural modification of lipid-protein assemblies.
Implication in cell maturation and atherogenesis. .................................. 132
5.8.4.2 Modulation of intracellular lipid signal transducers .............................. 133
5.8.4.3 Formation of bioactive oxygenated fatty acid derivatives ..................... 134
5.9 References .............................................................................................. 134
.................
6 Oxygenation of arachidonic Acid by cytochromes P-450 143
Ernst H . Oliw and Johanna Ericsson
6.1 Introduction ............................................................................................ 143
6.2 Early work on oxidation of fatty acids by cytochromes P-450 .............. 144
6.3 Oxygenation of arachidonic acid by cytochromes P-450 ....................... 146
6.3.1 Hydroxylation of o side chain ............................................................... 146
6.3.2 Epoxidation ............................................................................................ 147
6.3.3 Bisallylic hydroxylation and hydroxylation with double bond
migration ................................................................................................ 149
6.4 Metabolism of epoxides ......................................................................... 152
6.4.1 Epoxide hydrolases ................................................................................ 152
6.4.2 Incorporation into phospholipids ........................................................... 153
6.5. Analysis of arachidonic acid metabolites ............................................... 153
6.5.1 Radioimmunoassay ................................................................................ 153
6.5.2 GC-MS and LC-MS analyses. ................................................................ 154
6.5.3 Steric analysis of hydroxy fatty acids .................................................... 154
X Contents
6.5.4 Steric analysis of epoxy fatty acids and vicinal diols ............................. 155
6.6 Biological effects ................................................................................... 156
6.6.1 Kidney .................................................................................................... 156
6.6.2 Heart ....................................................................................................... 158
6.6.3 Vascular tree .......................................................................................... 158
6.6.4 Central nervous system and the pituitary ............................................... 159
6.6.5 Genital glands and endocrine organs ..................................................... 160
6.7 Summary ................................................................................................ 161
6.8 References ............................................................................................. 161
.................................................................................
7 Renal eicosanoids 169
Margarete Goppelt-Striibe and Joachim Fader
7.1 Renal prostanoids ................................................................................... 169
7.1.1 Localization of prostanoid biosynthesis in the kidney ........................... 170
7.1.2 Regulation of prostaglandin synthesis in mesangial cells ...................... 172
7.1.3 Cyclooxygenase expression in renal inflammation. ............................... 173
7.1.4 Prostanoid receptors ............................................................................... 173
7.1.4.1 TXA2 receptor ........................................................................................ 174
7.1.4.2 PGFza receptor ....................................................................................... 175
7.1.4.3 Prostacyclin (PG12)r eceptor .................................................................. 175
7.1.4.4 PGE? receptors ....................................................................................... 176
7.1.4.4.1 EP, receptors .......................................................................................... 176
7.1.4.4.2 EP2/EP4 receptors ................................................................................... 177
7.1.4.4.3 EP3 receptors .......................................................................................... 177
7.1.5 Vasoactive effects of prostanoids: relation to hypertension. .................. 178
7.1.6 Regulation of water and electrolyte transport by prostanoids:
clinical implications ............................................................................... 180
7.1.7 Cyclooxygenase inhibitors and the kidney. ............................................ 181
7.2 Renal leukotrienes .................................................................................. 181
7.2.1 Biosynthesis ........................................................................................... 181
7.2.3 Biological activity of leukotrienes in the kidney .................................... 182
7.3 Renal lipoxins ........................................................................................ 183
7.3.1 Biosynthesis of lipoxins ......................................................................... 183
7.3.2 Biological activity of lipoxins in the kidney .......................................... 184
7.4 Cytochrome P-450 enzyme-generated arachidonic acid metabolites. .... 185
7.4.1 P-450 arachidonic acid o-hydroxylases ................................................. 186
7.4.2 Renal epoxygenases ............................................................................... 186
7.4.3 Functional properties of 19- and 20-HETE ............................................ 187
7.4.4 Functional properties of epoxides .......................................................... 187
7.4.5 Monooxygenase products in animal models of renal hypertension ....... 188
7.4.6 P-450-catalysed arachidonic acid metabolism in man ........................... 189
7.5 Isoprostanes. ........................................................................................... 190
7.5.1 Generation of isoprostanes in the kidney ............................................... 190
7.5.2 Functional properties of isoprostanes. .................................................... 191
Contents XI
7.6 Perspective ............................................................................................. 192
7.7 References .............................................................................................. 192
.............................................
8 The role of eicosanoids in reproduction 199
H.P. Zahradnik. B . Wetzka and W.R.S chaler
8.1 Introduction ............................................................................................ 199
8.2 Female reproductive system ................................................................... 199
8.2.1 Ovarian function .................................................................................... 199
8.2. 1 . 1 Follicular phase: ovulation ..................................................................... 200
8.2.1.2 Luteal phase: luteolysis .......................................................................... 201
8.2.2 The Fallopian tube ................................................................................. 202
8.2.3 Menstruation .......................................................................................... 203
8.2.4 Endometriosis ......................................................................................... 207
8.3. Pregnancy ............................................................................................... 208
8.3.1 Implantation ........................................................................................... 208
8.3.2 Placenta .................................................................................................. 211
8.3.3 Pregnancy-induced hypertension and pre-eclampsia ............................. 214
8.3.4 Parturition .............................................................................................. 216
8.3.4.1 Cervical ripening .................................................................................... 218
8.3.4.2 Labor ...................................................................................................... 220
8.3.4.3 Pre-term labor ........................................................................................ 222
8.4 Male reproductive system ...................................................................... 223
8.4.1 Acrosome reaction ................................................................................. 224
8.4.2 Immunosuppressive actions of PGE ...................................................... 224
8.4.3 Erectile dysfunction ............................................................................... 224
8.5 References .............................................................................................. 225
........................
9 The role of eicosanoids in inflammation and allergy 233
Eva Wikstrom Jonsson and Sven-Erik Dahlkn
9.1 Introduction ............................................................................................ 233
9.2 Formation of eicosanoids in allergic inflammation ................................ 234
9.3 Biological activities and receptors with relevance for asthma
and allergic inflammation ...................................................................... 238
9.3.1 COX products ........................................................................................ 238
9.3.2 LTB4 ....................................................................................................... 239
9.3.3 Cysteinyl leukotrienes ............................................................................ 241
9.3.4 Lipoxins ................................................................................................. 243
9.4 Cysteinyl leukotrienes as mediators of allergen-induced airway
obstruction and bronchial hyper-responsiveness .................................... 243
9.4.1 Biological activity .................................................................................. 244
9.4.2 Endogenous formation ........................................................................... 244
9.4.3 Influence of inhibitors of leukotriene synthesis or CysLT, receptor
